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. 2011 Dec 1;470(7):1879–1884. doi: 10.1007/s11999-011-2191-5

Is Monocyte Chemotactic Protein 1 Elevated in Aseptic Loosening of TKA?: A Pilot Study

Vinod Dasa 1,✉, Jill M Kramer 2, Sarah L Gaffen 4, Keith L Kirkwood 3, William M Mihalko 5,6
PMCID: PMC3369079  PMID: 22131127

Abstract

Background

Failure of TKA from aseptic loosening is a growing concern, as TKA is performed with increasing frequency. Loosening is multifactorial and may be associated with elevated inflammatory cytokines in addition to biomechanical failure.

Questions/purposes

We asked whether proinflammatory cytokines and chemokines are elevated in synovial fluid from patients undergoing revision surgery as compared to those with osteoarthritis (OA) or rheumatoid arthritis (RA).

Methods

We obtained synovial fluid samples from 20 patients: six with aseptic loosening of TKA (all with bone loss), 10 with primary OA, and four with RA. A panel of cytokines/chemokines was screened using a SearchLight® Array (Pierce Biotechnology, Rockford, IL, USA) in one revision sample. Using these data, we assayed the synovial fluids for monocyte chemotactic protein 1 (MCP-1) by ELISA.

Results

We observed an increase in synovial MCP-1 levels in samples from patients planned for TKA revision compared to those with OA or RA. In patients undergoing revision arthroplasty, the mean (± SD) MCP-1 concentration was 21,233 ± 18,966 pg/mL (range, 1550–50,657 pg/mL; n = 6). In patients with OA, the mean MCP-1 level was 3012 ± 3321 pg/mL. In patients with RA, the mean MCP-1 concentration was 690 ± 561 pg/mL.

Conclusions

All patients undergoing revision TKA showed elevated concentrations of MCP-1 compared to patients with OA and RA, suggesting MCP-1 may serve as a potential marker or predictor of bone loss in patients undergoing revision surgery.

Clinical Relevance

MCP-1 may be a novel biomarker in patients showing early symptoms of aseptic loosening of TKA.

Introduction

An emerging role for inflammatory cytokines in bone metabolism has recently been recognized [3, 8]. Numerous inflammatory cytokines drive osteoclast maturation, leading to a population of cells with bone-resorbing capabilities. Specifically, tumor necrosis factor α (TNF-α) and interleukin (IL)-1β, IL-6, and IL-17 all have a role in an inflammatory cascade leading to bone loss. Conversely, many cytokines and other factors inhibit bone loss, such as osteoprotegerin (OPG), IL-4, and IL-10 [9, 20, 31, 32, 39]. In the absence of disease, cytokines work in a balanced fashion to oppose each other’s actions, maintaining normal bone mass through continual turnover. However, in pathologic states, this balance is perturbed, leading to net bone loss.

The causative roles of cytokines and chemokines in disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA) are well documented [3, 10, 25]. However, less is known about the relationship between inflammatory cytokines and aseptic loosening of implants in TKA, although studies have detected the presence of numerous cytokines in these patients (Table 1). Patients who undergo TKA are at risk of aseptic loosening, thus needing revision TKA. One long-term study demonstrated 18.3% of all knee revision surgeries failed. Of these, 4.9% failed due to aseptic loosening of the TKA [23]. Aseptic loosening is a chronic inflammatory state secondary to particulate wear debris produced by the implants. This wear debris stimulates an inflammatory cascade that may lead to bone loss and subsequent implant loosening.

Table 1.

Cytokines and chemokines in aseptic loosening of total joint arthroplasty

Cytokine Site Cytokine source Study
IL-8 Hip Pseudocapsular tissue
Synoviallike interface membrane		 Lassus et al. [21]
IL-6 Hip Pseudosynovial tissue
Synoviallike interface membrane		 Konttinen et al. [18]
IL-1β Hip Synovium Clarke et al. [4]
IL-6 Knee
IL-8
IL-10
IL-6 Hip Synovium Beraudi et al. [2]
IL-8 Sabokbar and Rushton [29]
IL-8 Hip Serum and synovium Tanaka et al. [35]
IL-1β Hip Serum Granchi et al. [12]
IL-6
GM-CSF
M-CSF Hip Synoviumlike interface tissue and synovium Takei et al. [34]
M-CSF Hip Synoviallike membrane Xu et al. [41]
IL-1α Hip Interfacial membrane Shanbhag et al. [33]
IL-1α Hip Pseudosynovial membrane Westacott et al. [38]
IL-1β
IL-1β Hip Membranous tissue Jiranek et al. [15]
PDGF
IL-12 Hip Pseudosynovial fluid Inomoto et al. [13]
IL-11 Hip Pseudocapsular tissue Xu et al. [42]
IL-15 Hip Interface membrane Revell and Jellie [27]
Saeed and Revell [30]
TGF-β1 and 2 Hip Pseudocapsular tissue Konttinen et al. [17]
TNF-α Hip Synoviallike membrane Xu et al. [40]
MCP-1 Hip Periprosthetic tissue Nakashima et al. [24]
MIP-1α
MCP-1 Knee Synovial fluid Current study
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IL = interleukin; GM-CSF = granulocyte-macrophage colony-stimulating factor; M-CSF = macrophage colony-stimulating factor; PDGF = platelet-derived growth factor; TGF = transforming growth factor; TNF = tumor necrosis factor; MCP = monocyte chemotactic protein; MIP = macrophage inflammatory protein.

While several in vitro studies have examined the role of monocyte chemotactic protein 1 (MCP-1) in the synovial tissues of patients with chronic wear debris-induced inflammation [6, 7, 11, 19, 24, 36], none assessed MCP-1 in synovial fluid of patients undergoing TKA revision surgery for aseptic loosening. Collectively, these in vitro studies demonstrate increased MCP-1 gene expression and protein associated with chronic wear debris. These studies focused on titanium [6, 7] and polymethylmethacrylate particles [24]. Fritz et al. [6, 7] performed analyses with human bone marrow-derived and osteosarcoma cells. Their studies determined that titanium particles caused increased IL-8 expression and activation of the NF-κB transcription factor, giving further insight into the osteoblast role in the pathogenesis of osteolysis. By studying granulomatous tissue retrieved during revision, Nakashima et al. [24] found MCP-1 expressed within this tissue. Moreover, antibodies to MCP-1 inhibited expression of this chemokine in cell culture medium [24]. Identification of inflammatory mediators in patients undergoing aseptic loosening of TKA is important for developing rational therapeutics aimed at mitigating wear debris-induced inflammation and subsequent bone loss. Currently, anticytokine therapies are used successfully to limit inflammation and bone loss in patients with RA [25]. Therefore, MCP-1 may be a therapeutic target for mitigating aseptic loosening of prosthetic implants or a predictive marker of osteolysis in these individuals.

We therefore asked whether proinflammatory cytokines and chemokines are elevated in (1) synovial fluid from patients undergoing revision surgery (2) known inflammatory states such as RA and OA, and (3) patients undergoing revision surgery compared to patients with OA or RA.

Patients and Methods

We obtained synovial fluid samples from 20 patients: six undergoing revision arthroplasties with radiographic evidence of aseptic loosening, 10 with primary OA undergoing primary TKA, and four with self-reported RA. For patients undergoing revision arthroplasty, the primary diagnosis before the initial TKA was OA in all patients. We used the following criteria to identify absence of sepsis in the six patients: normal inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) and intraoperative frozen section demonstrating fewer than five neutrophils per high-power field. Intraoperatively, we inserted an 18-gauge needle into the knee before incision of the joint capsule to prevent blood and debris contamination. We centrifuged samples for 10 minutes at 2500 rpm to remove cells and other debris as previously described [1]. All patients undergoing revision TKA had cobalt-chromium components. One patient had a cobalt-chromium femoral component and titanium tibial base plate. The mean age of these six patients was 63 years (range, 37–78 years). There were four women and two men. Three patients were on NSAID treatment for at least 2 years before revision surgery. The average duration to revision surgery was 8.5 years (range, 2–12 years); one patient with aseptic loosening was less than 6 years from primary arthroplasty, and in that patient, we identified no factors for early failure. The mean age of the 10 patients undergoing primary TKA for OA was 72 years (range, 56–83 years). There were five women and five men. Nine patients were on NSAID treatment for at least 1 month before surgery. The four patients with self-reported RA all had radiographic evidence of RA. Their mean age was 59 years (range, 46–75 years). There were three women and one man. One patient was treated with steroids, and all patients reported taking NSAIDs. All patients in this study were ambulatory. This study was approved by the institutional review board with informed consent obtained from all patients.

Preoperatively we obtained AP and lateral knee radiographs in all patients. We recorded the Anderson Orthopaedic Research Institute (AORI) classification for osteolytic bone lesions [5]. The AORI classification is commonly used in revision knee arthroplasty to assess bone loss and its impact on implant stability. The classification progresses from minimal bone loss (Type 1) to substantial bone loss requiring a hinged prosthesis in certain circumstances (Type 3). All six patients undergoing revision had bone loss: two had femurs with F1 bone loss, and four F2 bone loss; five of the tibias had T2 bone loss, and one T1 bone loss.

We analyzed all 20 synovial fluid samples using LINCOplex® technology for simultaneous, multianalyte detection of human IL-1β, TNF-α, and IL-6 (LINCO Research Inc, St Charles, MO, USA). IL-17 and MCP-1 levels were determined by ELISA (Biosource, Camarillo, CA, USA; and BD Pharmingen, San Diego, CA, USA). All MCP-1 and IL-17 samples were analyzed in triplicate at 450 nm using a microplate reader (Bio-Rad Laboratories, Inc, Hercules, CA, USA). We confirmed the abilities of representative ELISA kits to detect cytokines in synovial fluid using positive controls included in each of the kits.

A SearchLight® Array (Pierce Biotechnology, Rockford, IL, USA) was performed using 50 μL of one of the samples of synovial fluid from the six patients undergoing revision TKA. Performing a SearchLight® Array on all six patients was cost prohibitive; thus, we chose one sample to assess whether there were any significant cytokine differences. The SearchLight® Array was a multiplexed sandwich ELISA for the quantitative measurement of up to 16 proteins per well. We visualized cytokines and chemokines using a chemiluminescent signal imaged with a charge-coupled device (CCD) camera. Using the SearchLight® CCD Imaging and Analysis System software, we calculated the values (in picograms per milliliter) for unknowns from standard curves based on the position of the spots and comparison of density values for unknown samples to density values for known standards.

Since the data were not normally distributed, we used the Kruskal-Wallis test to determine differences in the MCP-1 levels (from the ELISA) in the synovial fluid samples from patients with RA, OA, and revisions. On finding a significant difference across the three groups, we performed Bonferroni-adjusted pairwise comparisons (p < 0.017) using the Mann-Whitney test.

Results

In patients with revision TKA, the mean ± SD MCP-1 concentration was 21,233 ± 18,966 pg/mL (range, 1550–50,657 pg/mL) (Fig. 1A). Patients 2 and 5 had lower levels of MCP-1 relative to other patients. When we examined cytokine profiles in patients undergoing revision TKA, there was no detectable IL-1β (< 0.6 pg/mL) or IL-17 (< 2.0 pg/mL). However, TNF-α concentrations varied among patients with revisions, with a mean of 208 ± 506 pg/mL. Since none of these cytokines were consistently elevated in these patients, we performed a broad screen of inflammatory factors, using SearchLight® Array (Fig. 2). Expression of the chemokine MCP-1 was high in this representative patient. In subjects without inflammation, MCP-1 expression is ordinarily undetectable, and thus its high expression is indicative of inflammatory activity [28].

Fig. 1A–D.

Fig. 1A–D

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Elevated levels of MCP-1 occurred in patients undergoing revision surgery and some patients with OA. Graphs show the MCP-1 concentrations in synovial fluid of (A) patients undergoing revision surgery for aseptic loosening of TKA (n = 6), (B) patients with OA undergoing primary TKA (n = 10), and (C) patients with RA undergoing primary TKA (n = 4). All samples were analyzed in triplicate, and SDs are shown. (D) A compilation of MCP-1 data shows elevated MCP-1 in patients undergoing revision TKA for aseptic loosening (n = 6) as compared to patients with OA (n = 10) or RA (n = 4) undergoing primary TKA.

Fig. 2.

Fig. 2

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Screening of a large panel of cytokines and chemokines identifies high levels of MCP-1 in synovial fluid from a patient undergoing revision surgery for aseptic loosening of TKA. A SearchLight® Array (Pierce Biotechnology) was performed using 50 μL of synovial fluid from one patient undergoing revision (Patient 1). Concentrations of the indicated cytokines or chemokines are indicated. IFN-γ = interferon γ; IP-10 = 10-kDa IFN-γ-induced protein; MIP-1α = macrophage inflammatory protein 1α.

The mean MCP-1 concentration was 3012 ± 3321 pg/mL (range, 365–9032 pg/mL) for OA samples (Fig. 1B) and 690 ± 561 pg/mL (range, 303–1522 pg/mL) for RA samples (Fig. 1C). Patients with OA fell into two distinct subsets based on MCP-1 concentration: greater than 4000 pg/mL and less than 2500 pg/mL (Fig. 1B).

We found a difference (p = 0.004) in MCP-1 in revision, OA, and RA synovial fluid (Fig. 1D). Post hoc analysis with a Mann-Whitney test showed the mean concentration of MCP-1 in revision samples was larger (p = 0.011 and p = 0.014, respectively) than OA and RA samples. However, when comparing OA and RA, there was no difference (p = 0.104) between mean MCP-1 concentrations. The mean concentration of the high MCP-1 for the OA group (> 4000 pg/mL) was lower than that for patients with revisions: 7502 pg/mL versus 21,233 pg/mL, respectively. Cytokines typically associated with bone loss did not distinguish patients undergoing revision from patients with OA and RA.

Discussion

Inflammatory cytokines play well-established roles in the development and progression of chronic inflammation in diseases such as RA and to a lesser extent OA [10, 16]. A possible consequence of advanced arthritis is the need for TKA, which has the risk of developing the need for revision surgery from aseptic loosening. The relationship between specific cytokine expression and aseptic loosening is not well understood, and how these cytokines relate to pathology seen in OA and RA patients has not been examined. We therefore asked whether proinflammatory cytokines and chemokines are elevated in (1) synovial fluid from patients undergoing revision surgery, (2) known inflammatory states such as RA and OA, and (3) patients undergoing revision surgery compared to patients with OA or RA.

We acknowledge several limitations to our study. First, with such a small sample size, it was not possible to detect small but potentially important differences in inflammatory markers. However, given the large differences in MCP-1 values among groups, MCP-1 appears to be associated with osteolysis and bone loss. Second, this study lacks confirmatory pathology for patients with inflammatory arthropathy such as RA, although these patients did have radiographic evidence consistent with their reported disease state. Third, we observed a difference between the values found using SearchLight® Array and those found using ELISA. The sensitivities of both platforms differ, which explains the difference in values between the two assays. However, the absolute findings of elevated MCP-1 were consistent in both assays. Finally, it is difficult to obtain adequate controls to establish normality. To obtain a true control, synovial fluid from a pain-free, well-functioning arthroplasty would be needed. This would create ethical concerns owing to the small but real risk of infection. Further studies to correlate MCP-1 activity with degree of osteolysis would be valuable based on these preliminary findings.

Our findings suggest a role for MCP-1 in patients with failed TKA (Fig. 1). When compared to patients with OA and RA, those patients undergoing revision TKA had elevated synovial fluid MCP-1 levels. This is consistent with previous reports connecting bone loss and inflammation with elevated MCP-1 levels. Several in vitro studies have shown an association between wear debris and MCP-1 production [6, 7, 11, 19, 24, 36], but few in vivo studies have examined MCP-1 levels in patients undergoing revision TKA. Ishiguro et al. [14] demonstrated the MCP-1 transcript is expressed at the bone-cement interface tissue in patients with failed TKAs. Transient MCP-1 expression is also observed in a murine model of titanium particle-induced inflammation [37]. MCP-1 is also expressed in inflamed bone. Specifically, one study examined the role of MCP-1 in an inflammatory lesion in a murine mandible, where the number of MCP-1-expressing cells correlated with the number of monocytes, suggesting MCP-1 is an important mediator in the recruitment of these cells to inflamed bone [26].

The OA group fell into two distinct categories with respect to MCP-1 levels. While the majority of patients with OA had low levels of MCP-1, a distinct group demonstrated high MCP-1 levels (Fig. 1B). Importantly, one study [22] reported a negative correlation between MCP-1 and TNF-α levels and muscle strength in patients with OA, suggesting inflammatory cytokines, and MCP-1 in particular, have relevance to clinical disease parameters. These findings may indicate an important role for MCP-1 in certain patients with OA. Thus, it may be prudent to direct future investigation into MCP-1 profiles in primary TKA and OA to determine whether the higher-MCP-1 group correlates with earlier revision and a shorter survivorship of the primary surgery.

Acknowledgments

We thank Ms. Cathy Buyea of the State University of New York at Buffalo and Dr. Cristina Sison of the Feinstein Institute for Medical Research for assistance with statistical analyses.

Footnotes

The institution of one or more of the authors (SLG) has received funding from the NIH (AR054389); one author (JMK) was supported by an individual F30 grant from the NIH (DE014831); one author (KLK) was supported by the NIH (DE14460, DE18290, and RR017696). Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his or her institution approved or waived approval for the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at the State University of New York at Buffalo (Buffalo, NY, USA).

Vinod Dasa and Jill M. Kramer equally contributed to this work.

Contributor Information

Vinod Dasa, Email: vdasa@lsuhsc.edu.

William M. Mihalko, Email: wmihalko@campbellclinic.com.

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