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. Author manuscript; available in PMC: 2021 Oct 1.
Published in final edited form as: Osteoarthritis Cartilage. 2020 Jun 3;28(10):1303–1315. doi: 10.1016/j.joca.2020.05.009

Lubricin in experimental and naturally occurring osteoarthritis: a systematic review

AR Watkins , HL Reesink ‡,*
PMCID: PMC8043104  NIHMSID: NIHMS1600659  PMID: 32504786

Abstract

Summary

Objective:

Lubricin is increasingly being evaluated as an outcome measure in studies investigating posttraumatic and naturally occurring osteoarthritis. However, there are discrepancies in results, making it unclear as to whether lubricin is increased, decreased or unchanged in osteoarthritis. The purpose of this study was to review all papers that measured lubricin in joint injury or osteoarthritis in order to draw conclusions about lubricin regulation in joint disease.

Design:

A systematic search of the Pubmed, Web of Knowledge, and EBSCOhost databases for papers was performed. Inclusion criteria were in vivo studies that measured lubricin in humans or animals with joint injury, that investigated lubricin supplementation in osteoarthritic joints, or that described the phenotype of a lubricin knock-out model. A methodological assessment was performed.

Results:

Sixty-two studies were included, of which thirty-eight measured endogenous lubricin in joint injury or osteoarthritis. Nineteen papers found an increase or no change in lubricin and nineteen reported a decrease. Papers that reported a decrease in lubricin were cited four times more often than those that reported an increase. Fifteen papers described lubricin supplementation, and all reported a beneficial effect. Eleven papers described lubricin knock-out models.

Conclusions:

The human literature reveals similar distributions of papers reporting increased lubricin as compared to decreased lubricin in osteoarthritis. The animal literature is dominated by reports of decreased lubricin in the rat anterior cruciate ligament transection model, whereas studies in large animal models report increased lubricin. Intra-articular lubricin supplementation may be beneficial regardless of whether lubricin increases or decreases in OA.

Keywords: Megakaryocyte stimulating factor, Proteoglycan 4, Superficial zone protein, Joint lubrication

Introduction

Post-traumatic osteoarthritis (PTOA) causes significant morbidity in both humans and domesticated animal species1,2. Acute trauma, most commonly affecting the knee, shoulder or ankle, is generally the inciting cause of PTOA in humans and results in disruption of articular cartilage, bone, synovial membrane, joint capsule, and muscle3. Surgical intervention alone does not delay the development of PTOA, and current efforts are focused on investigating potential chondroprotective therapies4,5. Lubricin has been identified as an important joint homeostatic and cartilage lubricating molecule that may be altered in the PTOA joint6,7. Inflammation within the joint secondary to injury and changes in the concentration and composition of lubricating molecules such as lubricin and hyaluronic acid likely occur simultaneously and may result in increased friction and perpetuation of cartilage damage8.

Lubricin, also known as superficial zone protein, megakaryocyte stimulating factor, and proteoglycan 4 (PRG4), is a highly glycosylated mucin-like glycoprotein that functions in boundary lubrication of the joint9,10 and inhibits synovial membrane hyperplasia11,12. Lubricin/PRG4 is highly conserved across species and tissues, including kidney, lung, liver, heart, brain, muscle, tendon, small intestine, periodontal ligament, ocular surface, menisci, bone, cartilage, and synovial membrane1319. Based upon this broad distribution across tissues and the presence of several splice variants, lubricin likely has more complex biological roles beyond joint lubrication20. Perhaps the most convincing evidence of the critical role lubricin plays in joint homeostasis and lubrication are the phenotypes that result from loss of lubricin in humans and in rodent models. Camptodactyly-arthropathy-coxa vera-pericarditis syndrome (CACP) is a rare heritable condition in humans that results from a mutation in the PRG4 gene locus21. CACP results in precocial multi-joint failure characterized by synovial hyperplasia, finger joint contracture, abnormalities of the femur and pericarditis22. The histological effects caused by lubricin deficiency are more fully characterized in lubricin knockout (Prg4−/−) mice. These mice are born with normal joints but, as early as 2 weeks of age, develop polyarthropathy as evidenced by abnormal protein deposition on cartilage, degeneration of the cartilage surface, synovial hyperplasia, disappearance of superficial zone chondrocytes and increased friction coefficients11,23,24.

Although lubricin is essential for normal joint homeostasis, it is not clear how lubricin is regulated after traumatic joint injury nor what role it plays in age-related OA. Lubricin levels have been reported to decrease in rodent, guinea pig and rabbit anterior cruciate ligament transection models (ACLT)8,2536. Human studies examining soft tissue knee injuries have predominantly found decreased lubricin levels14,37,38, whereas lubricin is elevated after tibial plateau fracture and in end-stage arthritis3943. Studies examining PTOA models and naturally occurring injuries in larger domestic species, such as dogs and horses, have revealed increased lubricin after injury4451. It is not understood whether these differences arise from inherent variation in individual subjects52,53, injury type, joint biomechanics, species, tissue, assay used to measure lubricin or time of sampling as joint fluid composition fluctuates temporally post-injury.

OA studies utilizing human subjects are inherently difficult to control for due to variation in injury severity, difficulty in obtaining samples at regular intervals and difficulty in obtaining baseline or healthy control samples. Animal models, regardless of species, obviate many of these concerns. Rat and mouse models are commonly used due to the availability of uniform genetic strains, the ability to standardize injuries, rigidly control environmental factors and evaluate large sample sizes. Large animal models, while requiring more specialized infrastructure, offer more clinical relevance to humans. Rodent models and some human studies are limited by the inability to directly obtain synovial fluid (SF) from the joint, necessitating the use of SF lavage. In large animal models, arthroscopic evaluation and serial SF sampling including a baseline sample are possible due to the larger SF volumes as compared to ~1 μL in the murine knee54,55. Body weight and joint loading in clinically relevant models, such as the dog and horse, more closely approximate that of humans, though the quadruped stance does introduce some variation in distribution of loading56. Rodents and rabbits have been cited to spontaneously heal cartilage lesions while dogs, horses, and humans do not57. Based on these pertinent differences, there may be advantages in evaluating lubricin and studying lubricin supplementation in large animal models of OA.

The objective of this article was to systematically review the body of literature investigating lubricin quantification in joint injury and OA in both humans and animal models with the goal of determining if lubricin increases, decreases or remains unchanged post-injury. In addition, papers that described intra-articular lubricin supplementation and/or investigated lubricin/Prg4 murine knockout models were evaluated. Finally, an assessment of citation symmetry between the papers that cited an increase or decrease in lubricin post-injury was performed, and a methodological quality assessment was applied to papers that quantified lubricin.

Methods

Author disclosure

The authors of this review are English speaking veterinarians. The laboratory of one author performs research on lubricin in rat, horse, and dog models. All papers that fit the study criteria were included in this review in an effort to avoid citation or outcome reporting bias. Papers closely related to, but not meeting all inclusion criteria, were addressed in the discussion.

Search criteria

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed. All PRISMA-compliant searches were conducted on peer-reviewed literature with dates of inception prior to April 4, 2019 using the following databases: PubMed, Web of Science and EBSCOhost (Fig. 1). No language restrictions were applied in the search strategy, but only articles available in English were considered. Published studies and abstracts were included.

Fig. 1.

Fig. 1

Selection and inclusion process for papers in this review.

Inclusion criteria

Potential studies were considered eligible for inclusion if the following PICOS criteria were met. Participants: humans with naturally occurring osteoarthritis or joint injury; animals of any species, age or sex with naturally occurring osteoarthritis or joint injury or experimentally induced joint injury; animals with or without joint disease that received intra-articular lubricin supplementation; murine lubricin/Prg4 knockout models or murine models that over-expressed lubricin/PRG4. Interventions: lubricin/PRG4 was measured in cartilage, fibrocartilage, meniscus, SF or synovial membrane, by any method; any formulation of lubricin was supplemented intra-articularly; the phenotype of a genetically modified animal that was deficient in or over-expressed lubricin was described. Comparisons: control interventions included cadaver tissue, contralateral limb if unaffected by disease, alternate area of joint if unaffected by disease, healthy animal, sham surgery, sham injection, vehicle injection, affected joint pre-injury, and wild-type animal. Outcome: reported quantification of lubricin following natural or experimental injury compared to a control or baseline; reported gross morphology, histological evaluation, immunohistochemical or immunofluorescence analysis, biochemical analysis, radiological evaluation, gene expression, or behavior analysis following supplementation of lubricin; reported on phenotype resultant from genetic manipulation of the Prg4 locus. Study Design: controlled studies that assessed lubricin concentration, expression, and/or staining in the joint of humans with joint disease or animals with naturally or experimentally occurring joint disease; controlled studies that assessed the effect of intra-articular lubricin supplementation on osteoarthritis; controlled studies that described the phenotype of lubricin deficient animals.

Exclusion criteria

Studies in which lubricin was only quantified in cell culture media or serum/plasma were excluded, though studies could contain in vitro components as long as lubricin was measured from a non-cultured tissue or SF sample. Studies in which the insult to the joint was performed post-mortem were excluded. Studies in which the focus tissue was tendon/ligament or the joint being assessed was the temporomandibular joint were excluded, as were studies primarily focusing on inflammatory arthritis or antigen-induced arthritis.

Study selection

One reviewer screened the title and abstract of all search results eliminating obviously non-compatible articles. Two reviewers independently screened the remaining titles and abstracts. Thorough reading of the text was performed when the abstract suggested inclusion criteria would be met.

Assessment of methodological quality

The opportunity for bias and the quality of the experimental design were independently assessed by two separate reviewers based on a modified version of a previously published list of criteria (Supplementary data 1)58. If there were disagreements, they were resolved via discussion until a consensus was reached. If a particular evaluation criteria was not applicable, the final score was calculated without including that question in the total possible points achievable. Articles that utilized a contralateral limb or other non-independent control were considered casee-control studies in this review although to truly fit the category an independent control should be included.

Citation data

To gain an understanding of the impact made on this field by each of the thirty-eight papers included in Tables I and II, the number of times cited as of April 22, 2019 was determined using the Web of Knowledge search function. This value was then divided by the number of years in publication to produce a citations/year value. These values were then combined between papers with similar outcomes to obtain a sum citations/year value.

Table I.

Lubricin quantification in human joint disease. ELISA – enzyme-linked immunosorbent assay, IHC – immunohistochemistry, WB – Western blot, MS – mass spectrometry, SF – synovial fluid, OA – osteoarthritis, NA – not available, mo – months, ACL – anterior cruciate ligament, eOA – early osteoarthritis, lOA – late osteoarthritis.

Injury Assay
Time of sampling Control Outcome
ELISA IHC WB MS

39 Tibial plateau fracture 11 +/−9 days postinjury Contralateral knee SF (n=3); healthy human knee SF (n=3) [Lubricin] increased post-injury
40 Knee OA (varus malalignments) End stage OA Lateral “spared compartment” cartilage in varus knee joints (n=3) Lubricin staining increased in OA
41 Total knee arthroplasty End stage OA Histologically healthy knee cartilage; cartilage from radiographically normal cadaver knees (n=3) [Lubricin] increased in OA; lubricin staining increased in more severely affected areas of joint
42 Total knee arthroplasty End stage OAOA Observational OA progression cohort knee SF (n=173) Lubricin increased with decreasing joint space in age/sex-adjusted model
43 Total knee arthroplasty End stage Calf and adult bovine cartilage (n=NA) Lubricin staining increased in OA
59 Tibial plateau fracture 12–66 mo postinjury Contralateral knee SF (n=10) [Lubricin] unchanged
60 Total arthroplasty, knee and hip End stage OA Histologically normal areas of same menisci and labra (n=NA) Lubricin staining unchanged
61 Tibial osteotomy; total knee arthroplasty; meniscectomy with OA End stage OA; chronic OA Healthy human knee SF (n=NA) [Lubricin] unchanged; correlated with anteroposterior laxity, full flexion angle and range of knee motion
37 ACL injury 32–364 days postinjury Contralateral knee SF (n=30) [Lubricin] decreased post-injury
62 eOA; lOA eOA (arthroscopy) and lOA (arthroplasty) Human cadaver knee SF (n=16) [Lubricin] decreased in lOA
38 Meniscal injury 2 days post-injury Human cadaver menisci (n=9) Lubricin staining decreased post-injury
14 Meniscectomy with OA NA Human menisci and SF obtained 3 months post-ACL injury (n=9) Lubricin expression decreased in OA menisci and OA SF lavage samples

Table II.

Lubricin quantification in naturally occurring injuries and experimental animal models of osteoarthritis. ELISA – enzyme-linked immunosorbent assay, IF – immunofluorescence, WB – Western blot, PCR – polymerase chain reaction, MS – mass spectrometry, SF – synovial fluid, SM – synovial membrane, OA – osteoarthritis, OCD – osteochondrosis dissecans, wk – week, ACLT – anterior cruciate ligament transection, DMM – destabilization of the medial meniscus, MFC – medial femoral condyle, MCLT – medial collateral ligament transection, PCLT – posterior cruciate ligament transection, * – AlphaLISA.

Species Model Assay
Control Outcome (Lubricin)
ELISA IF/IHC WB PCR MS

48 Horse Cartilage defect Time 0 baseline sample SF [lubricin] increased post-injury
46 Horse Carpal osteochondral fragment model; naturally occurring carpal OA Contralateral sham-operated joint SF [lubricin] increased post-injury; SM lubricin staining increased post-injury; PRG4 expression increased in SM but decreased in cartilage post-injury
49 Horse Late stage OA; acute joint injury; OCD * Healthy equine joints SF [lubricin] increased post-injury (*AlphaLISA)
50 Horse Carpal osteochondral fragment model Contralateral sham-operated joint SF [lubricin] increased post-injury
47 Horse Carpal osteochondral fragment model, talar impact model, stifle cartilage defect model Time 0 baseline sample SF [lubricin] increased post-injury
51 Horse Naturally occurring carpal and fetlock injury; acute <3 wk, chronic > 3 wk Contralateral uninjured joints SF [lubricin] increased post-injury, with acute injury higher than chronic injury
45 Dog ACLT Healthy canine synovial fluid SF [lubricin] increased post-injury
44 Dog ACLT Contralateral non-operated joint Lubricin staining depth increased post-injury
63 Mouse DMM Non-operated mice; contralateral sham-operated joint Lubricin staining & Prg4 expression increased post-injury
64 Sheep MFC full thickness defect; fetal and adult Twin lamb joint, healthy adult sheep joint Fetal: PRG4 expression increased post-injury Adult: PRG4 expression not changed post-injury
65 Sheep ACLT/MCLT or lateral meniscectomy Contralateral unoperated joint, sham-operated joint SF [lubricin] not changed
67 Sheep Lateral meniscectomy Sham-operated sheep joints Lubricin staining and PRG4 expression decreased post-injury
25 Rat ACLT Sham-operated rat joint SF [lubricin] and staining decreased post-injury
26 Rat ACLT Contralateral non-operated joint I Lubricin staining and Prg4 expression decreased post-injury
66 Rat Naturally occurring age-related OA Young, healthy rat joint SF [lubricin], staining and protein expression decreased with age-related OA
34 Rat ACLT Non-operated rat joints SF [lubricin], staining, and protein expression decreased postinjury
27 Rat ACLT Non-operated rat joints SF [lubricin], lubricin staining, and Prg4 expression decreased post-injury
32 Rat ACLT Non-operated rat joints Lubricin staining and expression decreased post-injury
33 Rat ACLT Non-operated rat joints Lubricin staining decreased post-injury
31 Rat ACLT Non-operated rat joints Lubricin staining decreased post-injury
35 Rat, mouse ACLT Sham-operated mice and rat joints Lubricin staining and expression decreased in ACLT + vehicle-treated joints post-injury
36 Mouse ACLT Sham-operated or vehicle-injected mouse joints Lubricin staining decreased post-injury
30 Guinea pig ACLT Non-operated guinea pig joints, contralateral nonoperated joint SF [lubricin] and expression decreased post-injury
29 Guinea pig ACLT; naturally occurring age-related OA Non-operated guinea pig joints SF [lubricin] decreased post-injury
8 Rabbit ACLT & PCLT Non-operated rabbit joints, sham-operated joint SF [lubricin] decreased at weeks 2 & 3 post-injury compared to baseline & week 1 post-injury
28 Rabbit ACLT Non-operated rabbit joints, contralateral non-operated joint SF [lubricin] and Prg4 expression decreased post-injury

Results

The electronic data search identified 787 potentially relevant papers (Fig. 1). 683 papers, including ninety-one reviews, were excluded by title and abstract evaluation. The remaining 104 were assessed for eligibility. Ultimately, sixty-two papers satisfied the inclusion criteria, including twelve using human subjects and fifty using animal models [Fig. 2(A)]. Of the animal papers, twenty-six measured lubricin post-injury, fifteen examined lubricin supplementation in animal models, and eleven papers utilized a genetic model.

Fig. 2.

Fig. 2

Summary of studies selected for inclusion divided by species and study type. A) Total number of studies included in Tables IIV showing that the majority of studies investigated animal models. B) Total number of studies included in Tables IIV divided by species and study type. Human studies made up 19% of all included studies. Rodent studies were primarily supplementation and genetic model studies. C) Total number of studies that quantified lubricin (Tables I and II) divided by human and animal. Human studies comprised 31% of these studies. D) Studies that quantified lubricin divided by species displaying the diversity in animal models that have been used to quantify lubricin.

Twelve papers fit the inclusion criteria for human studies (Table I). Five showed an increase in lubricin post-injury3943, three showed no change5961, and four showed a decrease [Fig. 3(A)]14,37,38,62. Of the studies that showed an increase in lubricin, four characterized knee OA at the point of total arthroplasty and one examined tibial plateau fractures at approximately 11 days post-injury [Fig. 2(A)]. The three studies that found no change in lubricin had the most variation in injury type, which included tibial plateau fractures, arthroplasties and tibial osteotomies to treat end-stage joint disease, and meniscectomies with concurrent OA. Of the manuscripts that showed a decrease in lubricin, three characterized ACL or meniscal injuries within 1 year of injury, while one study examined knees at the time of arthroscopy (early OA) and arthroplasty (end-stage OA). Lubricin was measured in human studies primarily via ELISA and immunohistochemical staining, with infrequent use of immunoblotting and mass spectroscopy. Methodological assessment revealed variation in quality scores across human studies, with the percentage of total possible points ranging from 33 to 63% (Supplementary data 2). The majority of variation in quality scores between human studies was attributed to documentation of inclusion/exclusion criteria and the availability of appropriate controls which also resulted in overall lower scores for human papers compared to animal papers.

Fig. 3.

Fig. 3

Frequency distributions representing the number of manuscripts reporting a decrease, increase, or no change in lubricin organized by (A) injury type in humans (B) animal species, and (C) OA animal model with ACLT being compared against all other models.

Fifty papers fit the inclusion criteria for animal studies. Thirtyseven used rodent models, with a distribution of eighteen mouse studies, 15 rat studies and one study using both mice and rats. Sixteen described non-rodent models, with six horse models, three sheep models, two studies each using dog, guinea pig and rabbit models and one Yucatan mini-pig model [Fig. 2(B)]. Twenty-six papers quantified lubricin post-injury (Table II). Nine showed an increase in lubricin concentration, staining, or expression postinjury [Fig. 3(A)]4451,63. One study found mixed results with an increase in PRG4 expression in a cartilage defect model in fetal sheep but no change in adult sheep64. One study found no change in lubricin concentration in SF following ACLT or lateral meniscectomy in sheep65. Fifteen studies found a decrease in lubricin concentration, staining, or expression post-injury8,2536,66,67. The animal studies demonstrated more homogeneous and higher quality scores than the human studies, with the percentage of total possible points ranging from 71 to 94%, acknowledging that it is difficult to make direct comparisons between human studies and experimental animal studies (Supplementary data 3). The majority of the variation in quality scores between animal studies was attributed to the application of allocation sequences and the blinding of outcome assessors.

Studies that reported an increase in lubricin post-injury utilized diverse models, which included destabilization of the medial meniscus (1), ACLT (2), cartilage defect (3), carpal osteochondral fragmentation (3), naturally occurring injury/OA (3), osteochondrosis dissecans (1), and a talar impact model (1). Three studies that reported an increase in lubricin utilized more than one model. Studies that reported a decrease in lubricin post-injury were overrepresented by the ACLT model (13), with other models including naturally occurring OA (2), and lateral meniscectomy (1). One study that reported a decrease in lubricin utilized more than one model. Lubricin was measured primarily via immunohistochemistry (IHC) or immunofluorescence (IF) staining of articular cartilage and/or synovial membrane and ELISA, with less frequent use of immunoblotting and qRT-PCR.

The rodent, rabbit, and guinea pig studies revealed a decrease in lubricin post-injury 93% of the time, while 100% of the horse and dog studies revealed an increase in lubricin post-injury [Fig. 2(B)]. Studies that used sheep models represented all three lubricin outcomes. Studies that used ACLT as a model reported a decrease in lubricin post-injury 83% of the time, while the percentage decreased to 23% if any other model was evaluated [Fig. 2(C)]. These findings are confounded by the fact that 83% of ACLT studies were performed in rodent, rabbit, and guinea pig models. Eleven of the papers that quantified lubricin post-injury also evaluated lubricin post-injury in the face of an ancillary treatment (Supplementary data 4).

The number of citations per year for the thirty-eight papers included in Tables I and II are represented in Fig. 3(B). Human studies that reported a decrease in lubricin were cited twice as often as those that reported an increase. Animal studies that reported a decrease in lubricin were cited six times more often than those that reported an increase. The papers that reported no change in lubricin post-injury were infrequently cited.

Fifteen papers described intra-articular lubricin supplementation with two of the papers also quantifying lubricin post-injury (Table III)6,26,27,6873,7479. Of the papers that described intraarticular lubricin supplementation, five used mouse models, nine used rat models, and one used a Yucatan mini-pig model. Nine used ACLT as the injury model, three used destabilization of the medial meniscus, and one study each used the following: a mouse TGF-β receptor mutant model and rat models of ovariectomy, destabilization of the medial meniscus, and intra-articular monosodium urate monohydrate crystal injection. The treatments included PRG4 overexpression and intra-articular injection of a truncated recombinant human lubricin construct (LUB:1) or full-length recombinant human lubricin, lubricin derived from cultured human synoviocytes, or purified human SF lubricin. All papers found a beneficial effect of lubricin supplementation based on histological, morphological, functional and/or gene expression outcome measures.

Table III.

Lubricin supplementation in the OA joint. ACLT – anterior cruciate ligament transection, HDV – helper dependent adenoviral vector, OA – osteoarthritis, OARSI – osteoarthritis research society international, PTOA – post-traumatic osteoarthritis, IL-1ra – interleukin 1 receptor antagonist, IA – intraarticular, DMM – destabilization of the medial meniscus, AC – articular cartilage, DNIIR – dominant-negative mutant of TGF|3R2 (OA model), OVX – ovariectomized rat model, rhPRG4 – recombinant human lubricin/proteoglycan 4, MMP-13 – matrix metalloproteinase 13, TRAP – tartrate-resistant acid phosphatase, HSL – human synoviocyte lubricin, HSFL – human lubricin, GAG – glycosaminoglycans, CTX-II – carboxy-terminal telopeptides of type II collagen, MT – meniscal tear, ASI – aggrecanase specific inhibitor, MUM – monosodium urate monohydrate, hrs – hours, HA – hyaluronic acid, PBS – phosphate buffered saline.

Species Model Treatment Outcome following lubricin supplementation

6 Mouse ACLT Prg4 overexpression in cartilage (Col21a promoter) or Prg4 via HDV Prg4 overexpression decreased signs of age-related and post-traumatic OA, including preservation of cartilage volume, decreased OARSI score, increased expression of Col10a1 and Mmp13 and decreased functional impairment; gene transfer with HDV-Prg4 protected against PTOA and age-related OA based on decreased OARSI score and increased cartilage volume
68 Mouse ACLT Prg4 over-expression in cartilage (Col21a promoter) or Prg4 ± Il-1Ra via HDV Prg4 overexpression reduced age-related and post-traumatic OA; Prg4 expression inhibited transcriptional programs that promote cartilage catabolism and hypertrophy; IA injection of HDV expressing Prg4 protected against PTOA
69 Mouse ACLT IA HDV-Prg4 or 10mabHDV-Prg4 Both treatments improved OARSI scores and increased cartilage volume and surface area; 10mabHDV-Prg4 treated joints had lower OARSI scores and larger bone area covered by cartilage than HDV-Prg4 treated joints
70 Mouse ACLT or DMM IA HDV-NFκB-Il1ra and/or HDV-EF1-Prg4 Combined therapy increased expression of pro-anabolic and cartilage matrix genes; decreased catabolic gene and inflammatory mediator expression; preserved AC volume and surface area; prevented thermal hyperalgesia
71 Mouse DNIIR Prg4 overexpression via Col2a1 promoter Fewer missed steps; decreased cartilage fibrillation and OARSI scores; increased cartilage thickness
72 Rat OVX IA rhPRG4 at day 0or14 Decreased cartilage degeneration, OARSI score, proteoglycan loss, and staining for collagen X and MMP-13; increased lubricin expression; normalized bone remodeling; inhibited elevation of TRAP and Osterixpositive cells; rescued thickening of calcified cartilage zone; decreased vascular invasion of calcified cartilage
73 Rat DMM IA rhPRG4 1 or 3x/wk Decreased cartilage degeneration and cartilage lesion/degeneration width; facilitated boundary lubrication and decreased synovial cell adhesion; 3x/wk dosing increased benefit
74 Rat ACLT IA HSL or rhPRG4 or purified HSFL Decreased OARSI scores; increased lubricin staining and Prg4 expression; decreased fibrillation at cartilage surface with more superficial chondrocytes; decreased collagen type II degradation; no difference between treatments
75 Rat ACLT IA HSL Equalized weight distribution between hind legs; increased lubricin mRNA expression; increased lubricin staining to level of sham-operated joints; increased GAG content; decreased urinary CTX-II; OARSI score not different
76 Rat MT IA rhPRG4 ± ASI Decreased pain 4 wks post-injury and for 3 wks post-dose cessation; combined therapy decreased pain more than monotherapy
77 Rat MUM IA rhPRG4 At 6 h: supplementation normalized weight bearing and myeloperoxidase activity. At 24 h: no difference
78 Rat ACLT IA purified HSFL ± HA Decreased radiographic and histologic OA scores, increased SF [lubricin]; HA provided no added benefit
27 Rat ACLT IA rhPRG4 Increased lubricin staining in articular cartilage post-injury; decreased caspase-3 and MMP-13 staining
26 Rat ACLT IA purified HSFL ± exercise Increased lubricin staining in articular cartilage; increased SF [lubricin]; decreased urinary CTX-II levels and caspase-3 staining
79 Pig DMM IA rhPRG4 ± HA Decreased macroscopic OA scores; increased SF [lubricin]; decreased serum IL-1β; no difference between PBS and rhPRG4 + HA

Eleven papers utilized a murine Prg4 knock-out model (Table IV)11,23,24,8087. Four described the phenotype of knock-out mice at varying ages without any treatment. Two papers assessed the effects of genetically restoring lubricin expression at varying timepoints, including at pre-conception,1 week, 2 weeks, 2 months and 6 months of age. Five papers examined the effects of treatments, including cyclic loading, lubricin and systemic parathyroid hormone administration, on Prg4 null mice.

Table IV.

Phenotype and treatment effect of lubricin-null mouse models. Mo – month, AC – articular cartilage, SZ – superficial zone, wk – week, COF – coefficient of friction, MFC – medial femoral condyle, OA – osteoarthritis, WT – wild type, HTZ – heterozygote, IA – intra-articular, PTH – parathyroid hormone, SDF-1 – stromal cell-derived factor 1, FGF-2 – fibroblast growth factor-2, CTX-II – carboxy-terminal telopeptides of type II collagen.

Model Treatment Outcome/Phenotype

11 Prg4 null mice None Normal joints at birth. At 2–4 mo: abnormal protein deposition on AC; decreased SZ chondrocytes; synovial hyperplasia; abnormal calcification of tendons/sheaths
23 Prg4 null mice None Normal joints at birth. At 2 wks: irregular cartilage surface with disruption of parallel orientation of collagen fibrils; absence of lamina splendens. At 1 mo: increase in joint COF
24 Prg4 null mice None At 2 wks: Roughened cartilage surface. At 16 wks: decreased pericellular proteoglycans; increased COF. Adult: lower elastic modulus in articular cartilage
80 Prg4 null mice None At 10 wks: decreased live chondrocyte volume fraction in MFC; increased cartilage thickness in MFC, increased caspase-3 positive cells in MFC superficial and upper intermediate cartilage zones
81 Prg4 null mice Prg4 genetically restored at pre-conception or 3 wk, 2 mo, or 6 mo of age Rx: no joint disease with pre-conception restoration of Prg4; 3 wk restoration: increased caspase-3 activation and histological evidence of OA; 2 & 6 mo restoration: unchanged from Prg4 null littermates
82 Prg4 null mice Prg4 genetically restored at7or14 days of age Rx: restored joints unchanged from null joints in COF and histology; restored cartilage had decreased numbers of peroxynitrite and caspase-3 positive cells
83 Prg4 null mice Cyclic loading COF of null joints higher than WT or HTZ; Rx: upto4h of cyclicjoint loading increased null joint COF while WT and HTZ COF remained unchanged. At 26 h: all COF increased (larger increases in null and HTZ joints)
84 Prg4 null mice IA human lubricin Null joints showed mitochondrial dysregulation-mediated caspase activation and increased levels of peroxynitrite and superoxide; Rx: treatment prevented caspase-3 activation in AC and decreased whole joint friction
85 Prg4 null mice PTH Null mice showed increased peripheral blood neutrophils; decreased marrow B-lymphocytes; decreased SDF-1; Rx: PTH normalized findings
86 Prg4 null mice PTH Young: decreased growth plate hypertrophic zone height, trabecular bone, and serum bone formation markers; Adult: decreased trabecular and cortical bone, decreased tarsal range of motion, decreased liver and bone marrow FGF-2 mRNA; Rx: Young: no change; Adult: PTH increased bone mass and normalized FGF-2 mRNA
87 Prg4 null mice PTH Acellular material deposited on AC and menisci; increased AC degradation; increased serum [CTX-II]; decreased articular chondrocyte apoptosis; increased SDF-1 expression in synovium; irregularly contoured subchondral bone; Rx: PTH induced a secondary deposit overlaying the acellular material on the AC

Discussion

Combining human and animal studies, nineteen reported an increase or no change in lubricin in joint injury or OA, while nineteen reported a decrease in lubricin. Given the heterogenous nature of OA, with distinct phenotypes based on disease etiology (traumatic, metabolic and inflammatory) and individual characteristics (obesity, age and activity level), variability in OA models and disease likely contributes to significant variation in study outcomes88. Studies that evaluated rodent, rabbit, or guinea pig models (n = 18) found a decrease in lubricin in the PTOA joint 93% of the time, while papers investigating horses and dogs (n = 8) found an increase in lubricin 100% of the time. Similarly, studies in ACLT models reported a decrease in lubricin in the PTOA joint 83% of the time, while studies reporting on any other injury model reported a decrease in lubricin only 23% of the time. Injury type was associated with lubricin quantification outcome in human studies, with 3/4 of the studies that cited a decrease in lubricin reporting on a population of soft tissue injuries such as ACL tears and meniscal damage, while 4/5 of the studies that cited an increase in lubricin reported on a population with end-stage OA. Studies measuring lubricin used one or more of the following assays: immunohistochemistry/immunofluorescence (n = 21), ELISA (n = 18), immunoblotting (n = 9), polymerase chain reaction (PCR) (n = 11), or mass spectrometry (n = 2).

Of the thirty-eight papers that quantified lubricin, only four animal studies and one human study used three separate assays, permitting evaluation of multiple tissue types, including SF, articular cartilage and/or synovial membrane. Of these studies, two found an increase, and three found a decrease in lubricin post-injury. Immunohistochemical staining of articular cartilage and/or synovial membrane was more common in studies that reported a decrease in lubricin, while studies that reported an increase in lubricin were more likely to use ELISAs to determine the concentration in SF. This may be due to the fact that, in large animal models, where increased lubricin in PTOA joints is more frequently reported, undiluted SF aspirates can be easily obtained, while SF lavage is typically necessary to obtain measurements in rodent and small animal models. Even when normalizing for parameters such as urea, assays evaluating synovial lavage fluid are likely less accurate than evaluating direct SF aspirates54. Approximately half of the animal studies quantified lubricin at more than two timepoints, providing more information about temporal variation as compared to most human studies.

Although a previously described methodological assessment instrument for assessing the quality of drug studies was adapted for use in this review58, an ideal instrument is not available to compare the diverse study designs represented. Therefore, human and animal studies were assessed separately. Overall, the scores were higher in the animal studies than the human studies, highlighting the challenges with obtaining ideal human control tissues. For example, Musumeci et al. 2014 was penalized for the quality of the control population since patients with recent ACL injuries (~3 months post-traumatic rupture) were included as normal controls in comparison to patients with Kellgrene–Lawrence grade 2–3 knee OA. The authors concluded that lubricin is decreased in OA. In our opinion, ACL injury ~3 months prior to sampling would constitute a sub-acute traumatic injury, and it should be qualified that lubricin was decreased in chronic OA as compared to sub-acute ACL rupture rather than healthy knees.

Manuscripts that report a decrease in lubricin in OA are cited 4 times more often than those that do not, despite an approximately equal distribution of studies showing an increase or no change in lubricin. An explanation for this citation asymmetry is that loss of lubricin provides a direct motivation for evaluating the effects of lubricin supplementation in vivo. Lubricin supplementation resulted in improvement in all fifteen studies in which it was evaluated. Five studies used transgenic mice to evaluate long-term overexpression of Prg4, resulting in downregulation of transcriptional programs that promote cartilage catabolism and hypertrophy and upregulation of pro-anabolic and cartilage matrix genes. Four studies used purified human SF lubricin, and seven used variants of recombinant human lubricin. Histologic findings associated with lubricin supplementation included reduced OARSI scores, cartilage fibrillation, proteoglycan loss, and synovial cell adhesion and preservation of cartilage volume. Fourteen of the fifteen studies assessing lubricin supplementation were performed in rodents, with nine studies utilizing an ACLT model. Future studies in large animal models will be needed to determine if lubricin supplementation remains beneficial in models that report an increase in lubricin post-injury.

Lubricin is essential for boundary lubrication of articular cartilage; however, recent literature suggests that lubricin also has important biological functions, including modulating inflammation and protecting chondrocytes12,89. Lubricin, via its many O-linked glycans, is able to support contact loading and protect cartilage from shear stress90. Lubricin exists bound to the articular cartilage, likely via complexes with type II collagen, fibronectin, and cartilage oligomeric matrix protein (COMP), and it exists unbound in the SF as a reservoir91. Quantification and functional analysis of both cartilage-bound and free lubricin is an essential direction for future research. Approximately half of the mass of lubricin is determined by extensive O-linked glycosylation which may be modified in inflammation as evidenced by altered glycosylation patterns observed between normal joints, inflammatory arthritis, and joints with osteochondral fragments7,9,89. Lubricin inhibits inflammation by competitively binding to CD44 at the same site as hyaluronic acid, thereby decreasing synoviocyte proliferation and reducing expression of MMP1, MMP3, MMP13, IL-6 and IL-8 while increasing expression of TIMP2 and COX292,93. Lubricin binds to TLR2, TLR4, and TLR5 in an HA-independent manner and functions as an antagonist to reduce inflammation94,95. Lubricin/PRG4 also has important roles in joint development, with early cartilage and synovial membrane progenitor cells expressing Prg496. Recent data suggests that Prg4-expressing superficial zone chondrocytes may be a progenitor cell reservoir for deeper layers of cartilage97. A better understanding of lubricin’s anti-inflammatory, chondroprotective and lubricating functions will improve our ability to select appropriate patient populations, indications and timing for lubricin therapy.

Several studies were excluded from analyses due to absence of a control as defined by the inclusion criteria but still warrant discussion. Atarod et al. reported on an ovine ACLT model and found an increased SF lubricin concentration at two- and 4-weeks post-injury compared to 20-weeks post-injury; however, baseline pre-injury data was not available98. Similarly, Catterall et al. reported on acute knee injury in humans, demonstrating that lubricin was increased at the time of study enrollment (mean 15.2 days post-injury) as compared to at the time of arthroscopic repair (mean 47.6 days post-injury)99. Elsaid et al. reported on a decrease in SF lavage lubricin concentration from three to 7 weeks post-ACLT, but no comparison to a baseline or contralateral limb was included26. All of these papers interpreted the data as a decrease in lubricin in PTOA; however, in the absence of a pre-injury or healthy control comparison, the change demonstrated could be a return to normal level following an acute increase in lubricin post-injury.

Variation in the type of assays and reagents used to quantify lubricin and the lack of any commercially available, validated ELISAs are likely to contribute to discrepancies between studies. Immunohistochemistry is only semi-quantitative and cannot differentiate between increased lubricin that is produced locally within the articular cartilage and lubricin that has penetrated deeper into fibrillated, injured cartilage devoid of a surface zone. ELISAs are quantitative; however, ELISAs only measure free lubricin in the SF, which may be a mixture of secreted lubricin and lubricin that has become dissociated from articular cartilage. ELISAs, immunoblotting and IHC/IF can all be affected by variation in antibody reactivity to different lubricin glycosylation patterns100 and non-specific binding. PCR can provide supportive information; however, gene and protein concentrations do not always correlate well. More advanced glycomics assays, including MALDI-TOF mass spectrometry are becoming available; however, their expense limits high-volume sample analysis. Ideally, studies combine and find agreement across several methodologies including ELISA, IHC, and gene expression to increase study robustness while incorporating immunoblots to detect any degradation or fragmentation of the lubricin species being measured. Additionally, it is important that studies publish the details of their methodologies to assist with transparency and reproducibility. Particularly, listing the antibody used is essential as processing or cleavage of lubricin can result in conflicting changes in concentration when using different antibodies59.

Conclusion

Similar proportions of studies reported an increase or no change in lubricin in OA as compared to a decrease in lubricin; however, papers that reported a decrease in lubricin were cited 4 times more frequently. Large animal models were over-represented in studies that reported increased lubricin in OA, while rodent models were over-represented in studies that reported decreased lubricin in OA. Human studies were approximately evenly distributed between those reporting an increase or decrease in lubricin. Lubricin null mice demonstrate the importance of lubricin in joint homeostasis and attest how even a brief lubricin deficit can have long term degradative effects. Lubricin supplementation ameliorates age-related and post-traumatic OA based on gross, histological, and gene expression parameters. In addition to its lubricating function, lubricin has biological roles that may benefit the joint in OA, explaining why lubricin supplementation may be beneficial regardless of how lubricin content varies between models. Additional research is required to assess the value of lubricin supplementation in large animal joint injury models and to understand the biological roles of lubricin supplementation in the OA joint.

Supplementary Material

Supplementary Data 1
Supplementary Data 2
Supplementary Data 3
Supplementary Data 4

Fig. 4.

Fig. 4

Proportion of studies reporting a decrease, increase or no change in lubricin (A) in human and animal models, and (B) proportion of total citations per year since year of publication. There are an equal number of papers describing an increase or no change in lubricin as there are describing a decrease in lubricin post-injury; however, manuscripts reporting a decrease in lubricin were over-represented by 4-fold (2-fold for human, 6-fold for animal).

Acknowledgements

The authors would like to thank Kira Noordwijk, Lynn Johnson, Elizabeth Feeney, Larry Bonassar and Dave Putnam for helpful discussions related to the content of this manuscript.

Funding sources

This investigation was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases / National Institutes of Health K08AR068469 (HLR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.joca.2020.05.009.

Conflict of interest

Both authors supervise or work in a lab that investigates lubricin as it pertains to joint disease in horse, dog and rat models. Dr. Reesink has a provisional patent on the production and use of recombinant glycoproteins related to lubricin and similar mucins.

References

  • 1.Centers for Disease Control and Prevention. Arthritis: the nation’s most common cause of disability. Chronic disease at a glance reports. Natl Cent Chronic Dis Prev Heal Promot 2015:1–4. [Google Scholar]
  • 2.McIlwraith CW, Frisbie DD, Kawcak CE. The horse as a model of naturally occurring osteoarthritis. Bone Joint Res 2012;1(11):297–309, 10.1302/20463758.111.2000132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Carbone A, Rodeo S. Review of current understanding of posttraumatic osteoarthritis resulting from sports injuries. J Orthop Res 2017;35(3):397–405, 10.1002/jor.23341. [DOI] [PubMed] [Google Scholar]
  • 4.Chalmers PN, Mall NA, Moric M, Sherman SL, Paletta GP,Cole BJ, et al. Does ACL reconstruction alter natural history? J Bone Jt Surg 2014;96(4):292–300, 10.2106/JBJS.L.01713. [DOI] [PubMed] [Google Scholar]
  • 5.Chu CR, Millis MB, Olson SA. Osteoarthritis: from palliation to prevention AOA critical issues. J Bone Jt Surg – Am 2014;96(15):1–9, 10.2106/JBJS.M.01209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Ruan MZCC, Erez A, Guse K, Dawson B, Bertin T, Chen Y, et al. Proteoglycan 4 expression protects against the development of osteoarthritis. Sci Transl Med 2013;5(176):176ra34, 10.1126/scitranslmed.3005409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Svala E, Jin C, Rüetschi U, Ekman S, Lindahl A, Karlsson NG,et al. Characterisation of lubricin in synovial fluid from horses with osteoarthritis. Equine Vet J 2017;49(1):116–23, 10.1111/evj.12521. [DOI] [PubMed] [Google Scholar]
  • 8.Elsaid KA, Jay GD, Warman ML, Rhee DK, Chichester CO, Ka E, et al. Association of articular cartilage degradation and loss of boundary-lubricating ability of synovial fluid following injury and inflammatory arthritis. Arthritis Rheum 2005;52(6): 1746–55, 10.1002/art.21038. [DOI] [PubMed] [Google Scholar]
  • 9.Swann DA, Slayter HS, Silver FH. The molecular structure of lubricating glycoprotein-I, the boundary lubricant for articular cartilage. J Biol Chem 1981;256(11):5921–5. [PubMed] [Google Scholar]
  • 10.Jay GD. Characterization of a bovine synovial fluid lubricating factor. I. Chemical, surface activity and lubricating properties. Connect Tissue Res 1992;28(1–2):71–88, 10.3109/03008209209014228. [DOI] [PubMed] [Google Scholar]
  • 11.Rhee DK, Marcelino J, Baker M, Gong Y, Smits P, Lefebvre V, et al. The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth. J Clin Invest 2005;115(3):622–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Waller KA, Zhang LX, Elsaid KA, Fleming BC, Warman ML,Jay GD. Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis. Proc Natl Acad Sci U S A 2013;110(15):5852–7, 10.1073/pnas.1219289110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ikegawa S, Sano M, Koshizuka Y, Nakamura Y. Isolation, characterization and mapping of the mouse and human PRG4 (proteoglycan 4) genes. Cytogenet Cell Genet 2000;90(3–4): 291–7, 10.1159/000056791. [DOI] [PubMed] [Google Scholar]
  • 14.Musumeci G, Trovato FM, Loreto C, Leonardi R, Szychlinska MA, Castorina S, et al. Lubricin expression in human osteoarthritic knee meniscus and synovial fluid: a morphological, immunohistochemical and biochemical study. Acta Histochem 2014;116(5):965–72, 10.1016/j.acthis.2014.03.011. [DOI] [PubMed] [Google Scholar]
  • 15.Rees SG, Davies JR, Tudor D, Flannery CR, Hughes CE, Dent CM, et al. Immunolocalisation and expression of proteoglycan 4 ( cartilage superficial zone proteoglycan ) in tendon. Matrix Biol 2002;21:593–602. [DOI] [PubMed] [Google Scholar]
  • 16.Samsom ML, Morrison S, Masala N, Sullivan BD, Sullivan DA, Sheardown H, et al. Characterization of full-length recombinant human Proteoglycan 4 as an ocular surface boundary lubricant. Exp Eye Res 2014;127:14–9. [DOI] [PubMed] [Google Scholar]
  • 17.Leonardi R, Loreto C, Talic N, Caltabiano R, Musumeci G. Immunolocalization of lubricin in the rat periodontal ligament during experimental tooth movement. Acta Histochem 2012;114(7):700–4, 10.1016/j.acthis.2011.12.005. [DOI] [PubMed] [Google Scholar]
  • 18.Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res 1999;17(1):110–20, 10.1002/jor.1100170117. [DOI] [PubMed] [Google Scholar]
  • 19.Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys 1994;311(1):144–52, 10.1006/abbi.1994.1219. [DOI] [PubMed] [Google Scholar]
  • 20.Sun Y, Berger EJ, Zhao C, An K-N, Amadio PC, Jay G. Mapping lubricin in canine musculoskeletal tissues. Connect Tissue Res 2006;47(4):215–21, 10.1080/03008200600846754. [DOI] [PubMed] [Google Scholar]
  • 21.Mannurita SC, Vignoli M, Bianchi L, Kondi A, Gerloni V,Breda L, et al. CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort. Eur J Hum Genet 2014;22(2):197–201, 10.1038/ejhg.2013.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Marcelino J, Carpten J, Suwairi W, Gutierrez O, Schwartz S, Robbins C, et al. CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Nat Genet 1999;23(3):319–22. [DOI] [PubMed] [Google Scholar]
  • 23.Jay GD, Torres JR, Rhee DK, Helminen HJ, Hytinnen MM,Cha C-J, et al. Association between friction and wear in diarthrodial joints lacking lubricin. Arthritis Rheum 2007;56(11):3662–9, 10.1002/art.22974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Coles JM, Zhang L, Blum JJ, Warman ML, Jay GD, Guilak F, et al. Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4. Arthritis Rheum 2010;62(6):1666–74, 10.1002/art.27436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Elsaid KA, Machan JT, Waller K, Fleming BC, Jay GD, Ka E, et al. The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor alpha on chondroprotection in an animal model. Arthritis Rheum 2009;60(10):2997–3006, 10.1002/art.24800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Elsaid KAA, Zhang L, Waller K, Tofte J, Teeple E, Fleming BCC, et al. The impact of forced joint exercise on lubricin biosynthesis from articular cartilage following ACL transection and intra-articular lubricin’s effect in exercised joints following ACL transection. Osteoarthritis Cartilage 2012;20(8):940–8, 10.1016/j.joca.2012.04.021. [DOI] [PubMed] [Google Scholar]
  • 27.Elsaid KAA, Zhang L, Shaman Z, Patel C, Schmidt TAA, Jay GDD. The impact of early intra-articular administration of interleukin-1 receptor antagonist on lubricin metabolism and cartilage degeneration in an anterior cruciate ligament transection model. Osteoarthritis Cartilage 2014;23(1): 114–21, 10.1016/j.joca.2014.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Raleigh ARR, Cravotta MJJ, Garcia JJJ, Schumacher BLL, Kato K, Firestein GSS, et al. Decreased synovial fluid proteglycan-4 concentration in ACL-transected knee joints is due to a dynamic imbalance in biosynthesis, clearance, and effusion. Abstract. Osteoarthritis Cartilage 2018;26(1):S397, 10.1016/j.joca.2018.02.770. [DOI] [Google Scholar]
  • 29.Wei L, Fleming BC, Sun X, Teeple E, Wu W, Jay GD, et al. Comparison of differential biomarkers of osteoarthritis with and without posttraumatic injury in the Hartley Guinea pig model. J Orthop Res 2010;28(7):900–6, 10.1002/jor.21093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Teeple E, Elsaid KA, Fleming BC, Jay GD, Aslani K, Crisco JJ, et al. Coefficients of friction, lubricin, and cartilage damage in the anterior cruciate ligament-deficient Guinea pig knee. J Orthop Res 2008;26(2):231–7, 10.1002/jor.20492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Castrogiovanni P, Di Rosa M, Ravalli S, Castorina A, Guglielmino C, Imbesi R, et al. Moderate physical activity as a prevention method for knee osteoarthritis and the role of synoviocytes as biological key. Int J Mol Sci 2019;20(3):511, 10.3390/ijms20030511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Szychlinska MA, Trovato FM, Di Rosa M, Malaguarnera L,Puzzo L, Leonardi R, et al. Co-expression and Co-localization of cartilage glycoproteins CHI3L1 and lubricin in osteoarthritic cartilage: morphological, immunohistochemical and gene expression profiles. Int J Mol Sci 2016;17(3):1–19, 10.3390/ijms17030359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Szychlinska MA, Castrogiovanni P, Trovato FM, Nsir H, Zarrouk M, Lo Furno D, et al. Physical activity and Mediterranean diet based on olive tree phenolic compounds from two different geographical areas have protective effects on early osteoarthritis, muscle atrophy and hepatic steatosis. Eur J Nutr 2018, 10.1007/s00394-018-1632-2.0. [DOI] [PubMed] [Google Scholar]
  • 34.Musumeci G, Trovato FM, Pichler K, Weinberg AM, Loreto C, Castrogiovanni P. Extra-virgin olive oil diet and mild physical activity prevent cartilage degeneration in an osteoarthritis model: an in vivo and in vitro study on lubricin expression. J Nutr Biochem 2013;24(12):2064–75. [DOI] [PubMed] [Google Scholar]
  • 35.Cui Z, Crane J, Xie H, Jin X, Zhen G, Li C, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-beta activity and H-type vessel formation in subchondral bone. Ann Rheum Dis 2016;75(9):1714–21, 10.1136/annrheumdis-2015-207923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Ji B, Zhang Z, Guo W, Ma H, Xu B, Mu W, et al. Isoliquiritigenin blunts osteoarthritis by inhibition of bone resorption and angiogenesis in subchondral bone. Sci Rep 2018;8(1):1721, 10.1038/s41598-018-19162-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Elsaid KA, Fleming BC, Oksendahl HL, Machan JT, Fadale PD, Hulstyn MJ, et al. Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury. Arthritis Rheum 2008;58(6):1707–15, 10.1002/art.23495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Musumeci G, Loreto C, Carnazza ML, Cardile V, Leonardi R. Acute injury affects lubricin expression in knee menisci: an immunohistochemical study. Ann Anat 2013;195(2):151–8, 10.1016/j.aanat.2012.07.010. [DOI] [PubMed] [Google Scholar]
  • 39.Ballard BL, Antonacci JM, Temple-Wong MM, Hui AY, Schumacher BL, Bugbee WD, et al. Effect of tibial plateau fracture on lubrication function and composition of synovial fluid. J Bone Jt Surgery-American 2012;94(10), 10.2106/JBJS.K.00046.e64-1-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Leblanc KT, Walcott ME, Gaur T, O’Connell SL, Basil K, Tadiri CP, et al. Runx1 activities in superficial zone chondrocytes, osteoarthritic chondrocyte clones and response to mechanical loading. J Cell Physiol 2015;230(2):440–8, 10.1002/jcp.24727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Neu CP, Reddi AH, Komvopoulos K, Schmid TM, Di Cesare PE. Increased friction coefficient and superficial zone protein expression in patients with advanced osteoarthritis. Arthritis Rheum 2010;62(9):2680–7, 10.1002/art.27577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Ritter SY, Collins J, Krastins B, Sarracino D, Lopez M, Losina E, et al. Mass spectrometry assays of plasma biomarkers to predict radiographic progression of knee osteoarthritis. Arthritis Res Ther 2014;16(5):1–8, 10.1186/s13075-014-0456-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Zhang D, Johnson LJ, Hsu H-P, Spector M. Cartilaginous deposits in subchondral bone in regions of exposed bone in osteoarthritis of the human knee: histomorphometric study of PRG4 distribution in osteoarthritic cartilage. J Orthop Res 2007;25(7):873–83, 10.1002/jor.20344. [DOI] [PubMed] [Google Scholar]
  • 44.Desrochers J, Amrein MW, Matyas JR. Microscale surfacefriction of articular cartilage in early osteoarthritis. J Mech Behav Biomed Mater 2013;25:11–22, 10.1016/j.jmbbm.2013.03.019. [DOI] [PubMed] [Google Scholar]
  • 45.Wang Y, Gludish D, Hayashi K, Todhunter RJ, Krotscheck U, Johnson PJ, et al. Synovial fluid lubricin increases in canine cruciate ligament rupture. Abstract. Osteoarthritis Cartilage 2019;27:S470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Reesink HL, Watts AE, Mohammed HO, Jay GD, Nixon AJ. Lubricin/proteoglycan 4 increases in both experimental and naturally occurring equine osteoarthritis. Osteoarthritis Cartilage 2017;25(1):128–37, 10.1016/j.joca.2016.07.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Peal BT, Gagliardi R, Su J, Fortier LA, Delco ML, Nixon AJ, et al. Synovial fluid lubricin and hyaluronan are altered in equine osteochondral fragmentation, cartilage impact injury and full-thickness cartilage defect models. J Orthop Res 2020, 10.1002/jor.24597.0-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Grissom MJ, Temple-Wong MM, Adams MS, Tom M, Schumacher BL, McIlwraith CW, et al. Synovial fluid lubricant properties are transiently deficient after arthroscopic articular cartilage defect repair with platelet-enriched fibrin alone and with mesenchymal stem cells. Orthop J Sport Med 2014;2(7):1–10, 10.1177/2325967114542580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Matheson AR, Regmi SC, Jay GD, Scott WM, Schmidt TA, Schimdt TA. Proteoglycan 4 and hyaluronan in normal and diseased equine synovial fluid and serum. Abstract. ORS 2018 Annu Meet LB 2018. Poster No 2164, (2164):2164. [Google Scholar]
  • 50.Feeney E, Peal BT, Inglis JE, Su J, Nixon AJ, Bonassar LJ, et al. Temporal changes in synovial fluid composition and elastoviscous lubrication in the equine carpal fracture model. J Orthop Res March 2019, 10.1002/jor.24281.jor.24281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Antonacci JM, Schmidt TA, Serventi LA, Cai MZ, Shu YL, Schumacher BL, et al. Effects of equine joint injury on boundary lubrication of articular cartilage by synovial fluid: role of hyaluronan. Arthritis Rheum 2012;64(9):2917–26, 10.1002/art.34520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Irwin RM, Feeney E, Secchieri C, Galesso D, Cohen I, Oliviero F, et al. Distinct tribological endotypes of pathological human synovial fluid reveal characteristic biomarkers and variation in efficacy of viscosupplementation at reducing local strains in articular cartilage. Osteoarthritis Cartilage 2020, 10.1016/j.joca.2020.02.029 (xxxx). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Ludwig TE, McAllister JR, Lun V, Wiley JP, Schmidt TA. Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: restoration through proteoglycan 4 supplementation. Arthritis Rheum 2012;64(12):3963–71, 10.1002/art.34674. [DOI] [PubMed] [Google Scholar]
  • 54.Seifer DR, Furman BD, Guilak F, Olson SA, Brooks III SC, Kraus VB. Novel synovial fluid recovery method allows for quantification of a marker of arthritis in mice. Osteoarthritis Cartilage 2008;16(12):1532–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Fowlie JG, Stick JA, Nickels FA. Chapter 99 stifle. In: Equine Surgery. W.B. Saunders; 2012:1419–42, 10.1016/B978-1-4377-0867-7.00099-5. [DOI] [Google Scholar]
  • 56.McCoy AM. Animal models of osteoarthritis: comparisons and key considerations. Vet Pathol 2015;52(5):803–18. [DOI] [PubMed] [Google Scholar]
  • 57.Ahern BJ, Parvizi J, Boston R, Schaer TP. Preclinical animal models in single site cartilage defect testing: a systematic review. Osteoarthritis Cartilage 2009;17(6):705–13, 10.1016/j.joca.2008.11.008. [DOI] [PubMed] [Google Scholar]
  • 58.Cho MK, Bero LA. Instruments for assesssing the quality of drug studies published in the medical literature. J Am Med Assoc 1994;272(2):101–4. [PubMed] [Google Scholar]
  • 59.Ceylan HH, Erdil M, Polat G, Kara D, Kilic E, Kocyigit A, et al. Does intra-articular fracture change the lubricant content of synovial fluid? J Orthop Surg Res 2015;10(1):1–6, 10.1186/s13018-015-0232-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Zhang D, Cheriyan T, Martin SD, Schmid TM, Spector M.Lubricin distribution in the menisci and labra of human osteoarthritic joints. Cartilage 2012;3(2):165–72, 10.1177/1947603511429699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Ogawa H, Matsumoto K, Terabayashi N, Kawashima K, Takeuchi K, Akiyama H. Association of lubricin concentration in synovial fluid and clinical status of osteoarthritic knee. Mod Rheumatol 2017;27(3):489–92, 10.1080/14397595.2016.1209829. [DOI] [PubMed] [Google Scholar]
  • 62.Kosinska MK, Ludwig TE, Liebisch G, Zhang R, Siebert H-C,Wilhelm J, et al. Articular joint lubricants during osteoarthritis and rheumatoid arthritis display altered levels and molecular species. PloS One 2015;10(5):1–18, 10.1371/journal.pone.0125192. Gualillo O, ed. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Nalesso G, Thomas BL, Sherwood JC, Yu J, Addimanda O,Eldridge SE, et al. WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis. Ann Rheum Dis 2017;76(1):218–26, 10.1136/annrheumdis-2015-208577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Ribitsch I, Mayer RL, Egerbacher M, Gabner S, Kańdułakańduła MM, Rosser J, et al. Fetal articular cartilage regeneration versus adult fibrocartilaginous repair: secretome proteomics unravels molecular mechanisms in an ovine model. Dis Model Mech 2018;11(7):1–11, 10.1242/dmm.033092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Barton KI, Ludwig TE, Achari Y, Shrive NG, Frank CB, Schmidt TA. Characterization of proteoglycan 4 and hyaluronan composition and lubrication function of ovine synovial fluid following knee surgery. J Orthop Res 2013;31(10): 1549–54, 10.1002/jor.22399. [DOI] [PubMed] [Google Scholar]
  • 66.Musumeci G, Castrogiovanni P, Trovato FM, Imbesi R, Giunta S, Szychlinska MA, et al. Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression. Scand J Med Sci Sports 2015;25(2): e222–30. [DOI] [PubMed] [Google Scholar]
  • 67.Young AA, McLennan S, Smith MM, Smith SM, Cake MA, Read RA, et al. Proteoglycan 4 downregulation in a sheep meniscectomy model of early osteoarthritis. Arthritis Res Ther 2006;8(2):4–9, 10.1186/ar1898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Ruan Z, Guse K, Erez A, Cerullo V, Dawson B, Heggeness M, et al. Prevention of osteoarthritis by combination of proteoglycan 4 and interleukin 1 receptor antagonist expression. J Bone Miner Res 2013;28(1). [Google Scholar]
  • 69.Ruan MZC, Cerullo V, Cela R, Clarke C, Lundgren-Akerlund E, Barry MA, et al. Treatment of osteoarthritis using a helperdependent adenoviral vector retargeted to chondrocytes. Mol Ther - Methods Clin Dev. 2016;3:1–8, 10.1038/mtm.2016.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Stone A, Grol MW, Ruan MZC, Dawson B, Chen Y, Jiang M-M, et al. Combinatorial Prg4 and Il-1ra gene therapy protects against hyperalgesia and cartilage degeneration in posttraumatic osteoarthritis Short Title: combination gene therapy to treat osteoarthritis. Hum Gene Ther 2019;30(2): 225–35, 10.1089/hum.2018.106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Chavez RD, Sohn P, Serra R. Prg4 prevents osteoarthritis induced by dominant-negative interference of TGF-ß signaling in mice. PloS One 2019;14(1):1–18, 10.1371/journal.pone.0210601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Cui Z, Xu C, Li X, Song J, Yu B. Treatment with recombinant lubricin attenuates osteoarthritis by positive feedback loop between articular cartilage and subchondral bone in ovariectomized rats. Bone 2015;74:37–47, 10.1016/j.bone.2014.12.065. [DOI] [PubMed] [Google Scholar]
  • 73.Flannery CR, Zollner R, Corcoran C, Jones AR, Root A, Rivera Bermudez MA, et al. Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin. Arthritis Rheum 2009;60(3):840–7, 10.1002/art.24304. [DOI] [PubMed] [Google Scholar]
  • 74.Jay GD, Fleming BC, Watkins BA, McHugh KA, Anderson SC, Zhang LX, et al. Prevention of cartilage degeneration and restoration of chondroprotection by lubricin tribosupplementation in the rat following anterior cruciate ligament transection. Arthritis Rheum 2010;62(8):2382–91, 10.1002/art.27550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Jay GD, Elsaid KA, Kelly KA, Anderson SC, Zhang L, Teeple E, et al. Prevention of cartilage degeneration and gait asymmetry by lubricin tribosupplementation in the rat following anterior cruciate ligament transection. Arthritis Rheum 2012;64(4):1162–71, 10.1002/art.33461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Rivera-Bermudez MA, Tejada J, Blanchet TJ, Soucy S, Savary L, Georgiadis K, et al. Treatment with an aggrecanase specific inhibitor and lubricin significantly reduces joint pain iini a rat model of post-traumatic arthritis. Abstract. Osteoarthritis Cartilage 2010;18(2):S50, 10.1016/S10634584(10)60124-0. [DOI] [Google Scholar]
  • 77.Qadri M, Jay GD, Zhang LX, Wong W, Reginato AM, Sun C, et al. Recombinant human proteoglycan-4 reduces phagocytosis of urate crystals and downstream nuclear factor kappa B and inflammasome activation and production of cytokines and chemokines in human and murine macrophages. Arthritis Res Ther 2018;20(1):192, 10.1186/s13075-018-1693-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Teeple E, Elsaid KA, Jay GD, Zhang L, Badger GJ, Akelman M,et al. Effects of supplemental intra-articular lubricin and hyaluronic acid on the progression of posttraumatic arthritis in the anterior cruciate ligament-deficient rat knee. Am J Sports Med 2011;39(1):164–72, 10.1177/0363546510378088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Waller KA, Chin KE, Jay GD, Zhang LX, Teeple E, McAllister S, et al. Intra-articular recombinant human proteoglycan 4 mitigates cartilage damage after destabilization of the medial meniscus in the yucatan minipig. Am J Sports Med 2017;45(7):1512–21, 10.1177/0363546516686965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Karamchedu NP, Tofte JN, Waller KA, Zhang LX, Patel TK, Jay GD. Superficial zone cellularity is deficient in mice lacking lubricin: a stereoscopic analysis. Arthritis Res Ther 2016;18(1):64, 10.1186/s13075-016-0967-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Hill A, Waller KA, Cui Y, Allen JM, Smits P, Zhang LX, et al. Lubricin restoration in a mouse model of congenital deficiency. Arthritis Rheum 2015;67(11):3070–81, 10.1002/art.39276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Larson KMM, Zhang L, Badger GJJ, Jay GDD. Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation. Osteoarthritis Cartilage 2017;25(9):1488–95, 10.1016/j.joca.2017.05.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Drewniak EI, Jay GD, Fleming BC, Zhang L, Warman ML, Crisco JJ. Cyclic loading increases friction and changes cartilage surface integrity in lubricin-mutant mouse knees. Arthritis Rheum 2012;64(2):465–73, 10.1002/art.33337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Waller KA, Zhang LX, Jay GD. Friction-induced mitochondrial dysregulation contributes to joint deterioration in Prg4 knockout mice. Int J Mol Sci 2017;18(6):1252, 10.3390/ijms18061252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Novince CM, Koh AJ, Michalski MN, Marchesan JT, Wang J, Jung Y, et al. Proteoglycan 4, a novel immunomodulatory factor, regulates parathyroid hormone actions on hematopoietic cells. Am J Pathol 2011;179(5):2431–42, 10.1016/j.ajpath.2011.07.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Novince CM, Michalski MN, Koh AJ, Sinder BP, Entezami P, Eber MR, et al. Proteoglycan 4: a dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism. J bone Miner Sci 2012;27(1):11–25, 10.1002/jbmr.508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Novince CM, Entezami P, Wilson CG, Wang J, Oh S, Koh AJ, et al. Impact of proteoglycan-4 and parathyroid hormone on articular cartilage. J Orthop Res 2013;31(2):183–90, 10.1002/jor.22207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage 2017;25(12):1926–41, 10.1016/j.joca.2017.08.009. [DOI] [PubMed] [Google Scholar]
  • 89.Estrella RPP, Whitelock JMM, Packer NHH, Karlsson NGG. The glycosylation of human synovial lubricin: implications for its role in inflammation. Biochem J 2010;429(2):359–67, 10.1042/BJ20100360. [DOI] [PubMed] [Google Scholar]
  • 90.Jay GD, Harris DA, Cha CJ. Boundary lubrication by lubricin is mediated by O-linked β(1–3)Gal-GalNAc oligosaccharides. Glycoconj J 2001;18(10):807–15, 10.1023/A:1021159619373. [DOI] [PubMed] [Google Scholar]
  • 91.Flowers SA, Zieba A, Örnros J, Jin C, Rolfson O, Björkman LI, et al. Lubricin binds cartilage proteins, cartilage oligomeric matrix protein, fibronectin and collagen II at the cartilage surface. Sci Rep 2017;7(1):1–11, 10.1038/s41598-017-13558-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Alquraini A, Jamal M, Zhang L, Schmidt T, Jay GD, Elsaid KA. The autocrine role of proteoglycan-4 (PRG4) in modulating osteoarthritic synoviocyte proliferation and expression of matrix degrading enzymes. Arthritis Res Ther 2017;19(1):89, 10.1186/s13075-017-1301-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Al-Sharif A, Jamal M, Zhang LX, Larson K, Schmidt TA, Jay GD, et al. Lubricin/proteoglycan 4 binding to CD44 receptor: a mechanism of the suppression of proinflammatory cytokine-induced synoviocyte proliferation by lubricin. Arthritis Rheum 2015;67(6):1503–13, 10.1002/art.39087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Alquraini A, Garguilo S, D’Souza G, Zhang LX, Schmidt TA, Jay GD, et al. The interaction of lubricin/proteoglycan 4 (PRG4) with toll-like receptors 2 and 4: an anti-inflammatory role of PRG4 in synovial fluid. Arthritis Res Ther 2015;17:353, 10.1186/s13075-015-0877-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Iqbal SMM, Leonard C, Regmi CS, De Rantere D, Tailor P, Ren G, et al. Lubricin/proteoglycan 4 binds to and regulates the activity of toll-like receptors in vitro. Sci Rep 2016;6(1): 18910, 10.1038/srep18910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Koyama E, Shibukawa Y, Nagayama M, Sugito H, Young B, Yuasa T, et al. A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev Biol 2008;316(1):62–73, 10.1016/j.ydbio.2008.01.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Kozhemyakina E, Zhang M, Ionescu A, Ayturk UM, Ono N, Kobayashi A, et al. Identification of a Prg4-expressing articular cartilage progenitor cell population in mice. Arthritis Rheum 2015;67(5):1261–73, 10.1002/art.39030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Loeser RF, Dyondi D, Sarkar A, Banerjee R, Lotz MK, Greene GW, et al. Cartilage boundary lubrication of ovine synovial fluid following anterior cruciate ligament transection: a longitudinal study. Osteoarthritis Cartilage 2015;67(2):200–1, 10.1074/jbc.M111.298968. [DOI] [PubMed] [Google Scholar]
  • 99.Catterall JB, Stabler TV, Flannery CR, Kraus VB. Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254). Arthritis Res Ther 2010;12(6):R229, 10.1186/ar3216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Ai M, Cui Y, Sy M-S, Lee DM, Zhang LX, Larson KM, et al. Antilubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints. PloS One 2015;10(2), 10.1371/journal.pone.0116237. e0116237. [DOI] [PMC free article] [PubMed] [Google Scholar]

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