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Journal of Orthopaedics logoLink to Journal of Orthopaedics
. 2023 May 30;42:24–29. doi: 10.1016/j.jor.2023.05.010

Evaluation of mechanistic serum and urine biomarkers for secondary osteoarthritis associated with developmental dysplasia of the hip☆

Preston N Wolfe b,c, Aaron M Stoker a,b, Brett D Crist a,b, Emily Leary a,b, Chantelle C Bozynski a,b, James L Cook a,b,∗
PMCID: PMC10435905  PMID: 37601815

Abstract

Objective

Determine measurable differences for mechanistic urine and serum biomarkers in patients with developmental dysplasia of the hip (DDH) prior to, and following, secondary hip osteoarthritis (OA) when compared to controls.

Design

Urine and serum were collected from individuals with developmental dysplasia of the hip (n = 39), prior to (Pre-OA DDH, n = 32) and following diagnosis of secondary hip OA (Post-OA DDH, n = 7), age-matched Pre-OA controls (n = 35), and age-matched Post-OA controls (n = 12). Samples were analyzed for protein biomarkers with potential for differentiation of hip status through a Mann-Whitney U test with a Benjamini-Hochberg correction.

Results

Several interleukin and degradation related proteins were found to be differentially expressed when comparing DDH-related hip status prior to and following diagnosis of hip OA. In addition, MCP-1 and TIMP-1 were significantly different between younger and older patients in the control cohorts.

Conclusion

These results provide initial evidence for serum and urine protein biomarkers that define clinically relevant stages of symptomatic DDH and its progression to secondary hip osteoarthritis categorized by known mechanisms of disease.

Level of evidence

III.

Keywords: Dysplasia, Osteoarthritis, Biomarker, Mechanism

1. Introduction

Developmental dysplasia of the hip (DDH) can be recognized as a musculoskeletal disorder in children, as well as a significant risk factor for development of symptomatic hip dysfunction in young adults that often progresses to secondary osteoarthritis (OA) of the hip in middle-aged to older patients.1, 2, 3 In fact, DDH has been associated with a greater than double the risk for total hip arthroplasty before the age of 40 years.4, 5, 6 However, DDH in children does not inevitably result in secondary OA and the pathomechanisms involved in the progression of DDH to hip dysfunction and secondary OA have not been fully elucidated.

Ideally, DDH is detected during infancy such that non-operative management can be effective at mitigating the associated biomechanical imbalances in the affected hip prior to skeletal maturity, preventing symptoms and progression of disease.7 Unfortunately, current infant screening methods for DDH do not consistently provide high sensitivity and specificity for early diagnosis and do not allow for reliable severity staging or decision-making regarding type or timing of interventions.8,9 As such, an increasing number of young individuals, especially females from 13 years of age to mid-thirties, are being diagnosed with symptomatic DDH when they present for hip pain associated with physical activities.10 Further, an increasing number of patients are being diagnosed and treated for early-onset hip OA determined to be secondary to DDH.11 These delayed and/or missed diagnoses of DDH significantly alter treatment options and outcomes, and result in significant burdens to young adult, middle-aged, and older patients, representing a major unmet need in healthcare.

Biomarkers measured in serum, urine, and synovial fluid have been investigated as a potential method for disease screening, diagnosis, and staging for joint disorders.12, 13, 14, 15 The systemic fluids, serum and urine, are targeted for development of clinically applicable biomarkers for DDH, and are of particular interest as these fluids are easy to obtain in a minimally- or non-invasive manner as standard of care.16, 17, 18 Recent studies have reported that panels of urine and/or serum biomarkers may be able to differentiate young adults with DDH from young adults with healthy hips and have important correlations with the progression of hip osteoarthritis based on radiographic severity.19, 20, 21, 22, 23, 24, 25 In related studies targeting canine hip dysplasia, collagen turnover and inflammatory related protein biomarkers measured in the serum and urine of 5-month-old dogs were reported to be effective for predicting hip status as dysplastic or healthy at 2 years of age.26,27 Based on the similarities between canine hip dysplasia and DDH in human patients,28,29 serum and urine protein biomarkers appear to have strong potential for addressing a critical unmet need in orthopaedics.

A key step toward this goal involves the elucidation of categories of disease mechanisms that are more prominent during the clinically relevant stages in the development and progression of DDH to symptomatic hip dysfunction and/or secondary hip OA. This would allow validation of clinically applicable and cost-efficient serum and/or urine biomarker panels for screening, diagnosis, and staging for DDH.30, 31, 32, 33 Therefore, the present study was designed to apply this approach to DDH by testing three null hypotheses: 1) Young (13–34 years old) DDH patients without radiographic hip degeneration (pre-OA DDH) will not have significant differences in concentrations of serum and/or urine protein biomarkers compared to middle-aged (35–54 years old) DDH patients with radiographic hip degeneration (post-OA DDH); 2) DDH patients will not have significant differences in concentrations of serum and/or urine protein biomarkers compared to age-matched healthy-hip controls; and 3) Concentrations of serum and/or urine protein biomarkers in patients with healthy hips will not be significantly influenced by patient age.

2. Patients and methods

2.1. Patient population

With IRB approval (IRB #2012192) and informed patient consent, blood and urine were collected from four human subject cohorts:

  • •

    Pre-OA DDH cohort (n = 32, 4 male and 28 female): Young (13–34 years old) patients with physician confirmed DDH prior to clinical or radiographic signs of secondary hip OA.

  • •

    Controls for Pre-OA DDH cohort (n = 35, 11 male and 24 female): Healthy-hip controls aged 13–34 years old with no clinical or radiographic signs of DDH.

  • •

    Post-OA DDH cohort (n = 7, 1 male and 6 female): Middle-aged adult (35–54 years old) patients with confirmed hip OA, secondary to DDH.

  • •

    Controls for Post-OA DDH cohort (n = 12, 2 male and 10 female): Healthy-hip controls 35–54 years old with no clinical or radiographic signs of DDH or hip OA.

Pre-OA and Post-OA DDH patients were recruited during scheduled clinical visits while controls for each patient population were recruited through community outreach. Patient sample collection was not controlled for time of day for the collection or prior voids in the day of collection. Exclusion criteria included incompetent adults, prisoners, patients with cancer or who have received cancer treatment within the past 6 months of the clinic visit, patients who had any surgery within the last 6 months of the clinic visit, history of previous hip surgeries, recent joint trauma to any joint, metabolic disorders, rheumatoid arthritis, corticosteroid injections within the last 6 months of the clinic visit, currently taking oral corticosteroids, serious organ diseases or failures, are pregnant or lactating, or syndromic diseases (e.g. Cystic fibrosis or multiple sclerosis). Diagnosis of DDH in the affected population was determined based on physical examination by a board-certified orthopaedic surgeon in conjunction with diagnostic imaging assessments of the hips, including anteroposterior, Dunn, false-profile, and lateral radiographic views. In addition, computed tomography (CT) was utilized to assess acetabular version and femoral torsion. Measurements of lateral center-edge angle, anterior center-edge angle, Tönnis angle, acetabular extrusion index, alpha angle, head sphericity, acetabular version, and femoral torsion were utilized for diagnosis by a board-certified orthopaedic surgeon. MRI was not included in diagnosis for DDH in this study based on standard of care practice. Control cohorts were comprised of volunteers with self-reported healthy hips based on medical history, physical and orthopaedic examinations, and lack of any symptoms related to the hips; these volunteers did not undergo any study-related diagnostic imaging.

2.2. Sample collection and storage

Blood and urine samples were collected from participants in clinic or prior to surgical intervention depending on patient preference and cohort. As such, collection time was not standardized for time of day or fasting status. Whole blood (2–6 ml) was collected by aseptic peripheral venipuncture in a Vacutainer Serum Tube (Becton, Dickinson and Company, Franklin Lakes, NJ) and urine (>4 ml) was collected by voluntary micturition. After sample collection, the fluids were immediately transported to an on-site laboratory for processing. Whole blood samples were centrifuged (1200×g, 10 min), followed by serum collection. Serum and urine samples were aliquoted and stored at −80 °C for subsequent analyses.

2.3. Protein analysis

Protein biomarkers were initially selected from those that were reported to be effective for predicting hip status as dysplastic or healthy in dogs based on serum and urine analyses.26,27 Final inclusion for use in the present study was based on commercially availability and validation for human use for proteins within key categories known to be involved in the pathomechanisms associated with DDH and hip OA: inflammation, degradation, tissue turnover, and bone remodeling processes.

Serum and urine samples were analyzed for concentrations of all protein biomarkers as follows. Cross linked C-telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II), procollagen I C-terminal propeptide (PICP) and procollagen II (PIICP) using commercially available enzyme-linked immunosorbent assays (ELISA) assays (ABclonal; Woburn, MA). The concentration of hyaluronan (HA), a disintegrin-like and metalloproteinase domain with thrombospondin motifs 4 (ADAMTS4) and ADAMTS5, receptor activator of NF-kappa B ligand (RANKL), and Cartilage Oligomeric Matrix Protein (COMP) in the samples were assessed using DuoSet ELISA assays according to the manufacturer's protocol (R&D Systems; Minneapolis, MN). Human Multiplex Luminex immunoassay were used to analyze matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, and MMP-13 (R&D System, Minneapolis. MN). Human bone metabolism multiplex Luminex immunoassay were used to analyze dickkopf-related protein 1 (DKK-1), osteoprotegerin (OPG), osteocalcin (OC), osteopontin (OPN), sclerostin (SOST), parathyroid hormone (PTH) (MilliporeSigma, Burlington, MA). Human cytokine/chemokine multiplex Luminex immunoassay were used to analyze fibroblast growth factor (FGF)-2, Fractalkine, interferon gamma (IFN-γ), growth-regulated oncogene-alpha (GRO-α), interleukin (IL)-1beta (1β), IL-1-receptor antagonist (1RA), IL-4, IL-6, IL-10, and IL-13, monocyte chemoattractant protein (MCP)-1 and MCP-3, platelet derived growth factor (PDGF)-AA and PDGF-AA/BB, macrophage inflammatory protein(MIP)-1 alpha (1α) and MIP-1 beta (1β), regulated on activation, normal T expressed and secreted (RANTES), tumor necrosis factor alpha (TNFα), vascular endothelial growth factor (VEGF) (MilliporeSigma, Burlington, MA). Human TIMP multiplex Luminex immunoassay bead panel 2 were used to analyze tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, TIMP-3, and TIMP-4 (MilliporeSigma, Burlington, MA) in serum and urine. The urine creatinine concentration was measured with the creatinine colorimetric assay (Cayman Chemical Company; Ann Arbor, MI), and was used to standardize the urinary concentrations obtained for the other assays.

2.4. Statistical analysis

Data were summarized and non-normality was determined using Shapiro-Wilk normality tests. Therefore, a Mann-Whitney U test with a Benjamini-Hochberg correction for multiple comparisons was performed to determine significant differences in biomarker concentrations associated with progression from hip dysplasia to secondary osteoarthritis (Pre-OA DDH vs Post-OA DDH), secondary osteoarthritis to healthy-hip controls (Post-OA DDH vs controls for Post-OA DDH), and age-related differences within healthy control samples (controls for Pre-OA DDH vs controls for Post-OA DDH). Significance was determined by a two-sided p < 0.05. Analysis was performed in R version 4.1.2 (R Core Team, 2021), tables were produced using the package ggpubr (v0.4.0; Kassambara, 2020), and figures were produced using the ggplot2 package (v3.3.5; Wickham H, 2016).

3. Results

3.1. Patient population

The Pre-OA DDH patient population had an average age of 23.2 years, and the respective control cohort had an average age of 24.8 years with no statistically significant difference between them (p = 0.338). The average BMI for the Pre-OA DDH cohort was 26.1 kg/m2, and the average BMI for the respective control cohort was 24.7 kg/m2 with no statistically significant difference between them (p = 0.353).

The Post-OA DDH patient population had an average age of 44.6 years, and the respective control cohort had an average age of 43.0 years with no statistically significant difference between them (p = 0.586). The average BMI for the Post-OA DDH cohort was 31.3 kg/m2, and the average BMI for the respective control cohort was 28.4 kg/m2 with no statistically significant difference between them (p = 0.423).

3.2. Differences in serum and urine biomarkers between Pre-OA DDH and Post-OA DDH cohorts

In the urine, Post-OA DDH was associated with significantly higher median concentrations of SOST (p = 0.027), MMP-7 (p = 0.039), and TIMP-3 (p = 0.018) when compared to the Pre-OA DDH cohort. (Fig. 1, Supplemental Table 1). In the serum, Post-OA DDH was associated with significantly lower median concentrations of FGF-2 (p = 0.027), MCP-3 (p < 0.001), IL-13 p = 0.003), IL-1RA (p = 0.001), IL-4 (p = 0.002), and IL-6 (p = 0.001) when compared to the Pre-OA DDH cohort. (Fig. 1, Supplemental Table 2).

Fig. 1.

Fig. 1

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Representative urine and serum biomarkers with significant differences in protein concentrations between the Pre-OA DDH cohort and the Post-OA DDH cohort with median and IQR denoted by the middle and end points of the “box” in the boxplot.

3.3. Differences in serum and urine biomarkers between Post-OA DDH and controls

In the urine, Post-OA DDH was associated with significantly higher median concentrations of PIICP (p = 0.048), FGF-2 (p = 0.013), and PDGF-AB/BB (p = 0.045) when compared to the respective healthy-hip controls (Fig. 2, Supplemental Table 1). In the serum, the Post-OA DDH was associated with significantly lower median concentrations of OC (p = 0.046), MCP-1 (p = 0.010), and MCP-3 (p = 0.043) when compared to the respective healthy-hip controls (Fig. 2, Supplemental Table 2).

Fig. 2.

Fig. 2

Open in a new tab

Representative urine and serum biomarkers with significant differences in protein concentrations between the Post-OA DDH cohort and their respective healthy hip controls with median and IQR denoted by the middle and end points of the “box” in the boxplot.

3.4. Differences in serum and urine biomarkers between younger and older control cohorts

In the urine, younger (13–34 years old) healthy-hip controls were associated with significantly higher median concentrations of MCP-1 (p = 0.031) and TIMP-1 (p = 0.02) when compared to older (35–54 years old) healthy-hip controls (Fig. 3, Supplemental Table 1). There were no significant differences between younger and older healthy-hip controls for serum concentrations of measured biomarkers (Supplemental Table 2).

Fig. 3.

Fig. 3

Open in a new tab

Representative urine biomarkers with significant differences in protein concentrations between the younger healthy hip controls and the older healthy hip controls with median and IQR denoted by the middle and end points of the “box” in the boxplot.

4. Discussion

The data from this study delineate significant differences in concentrations of serum and urine biomarkers between patients diagnosed with DDH prior to secondary hip OA (Pre-OA DDH) and those with hip OA secondary to DDH (Post-OA DDH), as well as between the Post-OA DDH patients and their healthy-hip control cohort. Further, there were significant differences in urine biomarker concentrations when comparing younger (13–34 years old) healthy-hip controls with older (35–54 years old) healthy-hip controls. Taken together, these data provide an initial foundation for categorizing potential diagnostic and staging biomarkers based on disease mechanisms that relate to the development and progression of symptomatic DDH and early-onset secondary hip OA. Further development and validation of these biomarkers has the potential to provide clinically applicable panels for screening, diagnosis, and staging for DDH towards addressing the delayed and/or missed diagnoses that can significantly alter treatment options and outcomes for young adult, middle-aged, and older patients with DDH.

When diagnosed prior to clinical and diagnostic imaging signs of secondary hip OA, DDH was associated with increases in catabolic (FGF-2) and inflammation related (MCP-3, IL-1RA, IL-4, IL-6, and IL-13) biomarkers, and decreases in degradation related (MMP-7), anti-degradative (TIMP-3), and bone metabolism (SOST) biomarkers when compared to DDH with secondary hip OA. While defined as a growth factor, FGF-2 has been reported to induce catabolic effects on human articular cartilage and in the setting of DDH may be involved in dysplastic and remodeling processes that occur in the affected hip prior to the development of secondary OA.34,35 MCP-3, also known as CCL7, has been reported to be an inflammatory cytokine which regulates the function of macrophages and chemotaxis of monocytes.36 One study reported an increase of MCP-3 in synovial biopsies of patients with meniscus pathology associated with increased inflammation scores, indicating its potential role in OA.37 IL-1RA is a potent IL-1 receptor antagonist that inhibits IL-1β induced inflammation in OA. IL-4 is protective against MMP-mediated proteoglycan degradation and IL-13 inhibits synovial-derived inflammatory stimuli.38, 39, 40, 41, 42 IL-6 is an inflammatory cytokine that has been reported to be increased in synovial fluid from joints with OA and cause suppressed collagen type II neo-synthesis, enhanced IL-1β-mediated proteoglycan degeneration, and induction of MMP-13.43, 44, 45 The increased concentrations of these biomarkers suggest that articular cartilage remodeling and joint laxity are capable of driving inflammatory and anti-inflammatory processes in the pre-OA phase of DDH in younger patients compared to the post-OA DDH group. As such, an “inflammatory profile” in a subsequently validated biomarker panel may discriminate pre-OA DDH from post-OA DDH.

MMP-7 is a matrilysin that degrades articular cartilage proteoglycans and is consistently upregulated in OA.46 In the present study, urine MMP-7 concentrations were higher in post-OA DDH compared to pre-OA DDH. In addition, TIMP-3, which is an anti-degradative enzyme that blocks MMPs and ADAMTS,47,48 was associated with increased urine concentrations in post-OA DDH compared to pre-OA DDH. Urine concentrations of the bone metabolism biomarker, SOST, were also higher for post-OA DDH compared to pre-OA DDH. Taken together, these data suggest a shift to articular cartilage degradation and bone remodeling pathways in the post-OA stages of DDH, suggesting that a “degradation-remodeling profile” in a subsequently validated biomarker panel may discriminate post-OA DDH from pre-OA DDH.

When comparing post-OA DDH to healthy-hip controls, urine PIICP, FGF-2, and PDGF-AB/BB concentrations were higher and serum OC, MCP-1, and MCP-3 concentrations were lower for patients with DDH and secondary hip OA. PIICP is the cleavage product of type II procollagen integration and has been described as an early biomarker for OA.49 As described, FGF-2 induces catabolic effects on human articular cartilage34,35 while mechanistic effects of PDGF-AB/BB in OA have not been well described to date, but may involve tissue remodeling processes.50,51 OC is a bone metabolism biomarker, suggesting that decreased concentrations in the post-OA DDH cohort may be related to impaired subchondral bone remodeling consistent with OA progression.52,53 In conjunction with decreased concentrations of MCP-1 and MCP-3,54 these data suggest that articular cartilage degradation and bone remodeling biomarkers can also distinguish patients with DDH and secondary hip OA from similarly aged patients with healthy hips.

When comparing biomarker concentrations in the healthy-hip control cohorts, there were age-related decreases in urinary MCP-1 and TIMP-1. A previous mouse study indicated that circulating MCP-1 was decreased with aging55 while age-related changes in serum or urine TIMP-1 concentrations have not been reported to the authors’ knowledge. These data suggest that MCP-1 and TIMP-1 concentrations must be analyzed in the context of aging for subsequent DDH biomarker assessments, while the other differentiating biomarkers identified in the present study are likely attributable to DDH-related hip status.

There are several limitations to this study that should be considered when interpreting and applying the results. The patient population studied was relatively small with a very limited number of subjects that were healthy-hip controls for the post-OA DDH. Although the patient population was predominantly female, this is consistent with the epidemiology of DDH.56, 57, 58 In addition, patient cohorts were considered only based on two selected age ranges (13–34 and 35–54 years), such that potentially confounding factors including comorbidities, body mass index, medications, and others were not controlled for in patient inclusion or analyses. Healthy patient populations were determined by medical history and self-reports without diagnostic imaging confirmation. Sample time of collection was not standardized, which may cause some variability in biomarker concentrations. However, this experimental design was intentional such that the translational application of biomarker panels to ‘real life’ patient populations was considered. Future studies should include a larger sample size with additional matching among cohorts to account for these limitations and conduct analyses that consider these confounders.

These results provide initial evidence for serum and urine protein biomarkers that define clinically relevant stages of symptomatic DDH and its progression to secondary hip osteoarthritis categorized by known mechanisms of disease. Further clinical assessment of the discriminatory capabilities, including effect size, of these proteins may allow for the development and validation of panels for screening, diagnosis, and staging for the growing number of young adult, middle-aged, and older patients with delayed and/or missed diagnoses of DDH. Ongoing studies in our laboratory are using receiver operator characteristic curve analyses to assess biomarker panels based on similar proteins elucidated from the present study to determine the presence of DDH in patients from a blood or urine sample.25 With more effective screening methods for DDH, clinicians will be empowered to accurately diagnosis and stage DDH prior to irreversible pathology such that decision-making regarding type and timing of preventative and therapeutic interventions can be evidence based.

Conflict of interest disclosure

No external funding was used in the execution of this study. Portions of these data were presented at the annual conference of the Orthopaedic Research Society Annual Meetings, February 8–11, 2020, Phoenix, AZ, and February 4–8, 2022, Tampa, Florida.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author statement

Conceptualization: B.D.C. and J.L.C.; Formal analysis: E.L.; Investigation: P.N.W., A.M.S., B.D.C., C.C.B. and J.L.C.; Resources: A.M.S. and J.L.C.; Supervision: A.M.S., B.D.C. and J.L.C.; Writing – original draft: P.N.W., A.M.S., B.D.C., E.L., C.C.B. and J.L.C.; Writing - review & editing: P.N.W. and J.L.C.

All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.

Footnotes

☆

This study was completed at the University of Missouri, Columbia, USA.

Supplementary data

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jor.2023.05.010.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Multimedia component 1
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Multimedia component 2
mmc2.docx (14.3KB, docx)

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