Radiographic Knee Osteoarthritis Progression Research Articles

The mediating role of synovitis in meniscus pathology and knee osteoarthritis radiographic progression

Meniscus pathologies (damage, extrusion) and synovitis are associated with knee osteoarthritis (KOA); however, whether synovitis mediates the relationship between meniscus pathologies and KOA radiographic progression remains unclear. We conducted an observational study in the Osteoarthritis Initiative (OAI) cohort, with a 48-month follow-up. Meniscus pathology and synovitis were measured by MRI osteoarthritis knee score (MOAKS) at baseline and 24 months, and a comprehensive synovitis score was calculated using effusion and Hoffa synovitis scores. The knee osteoarthritis radiographic progression was considered that Kellgren–Lawrence (KL) grade and joint space narrowing (JSN) grade at 48 months were increased compared to those at baseline. This study included a total of 589 participants, with KL grades mainly being KL1 (26.5%), KL2 (34.1%), and KL3 (30.2%) at baseline, while JSN grades were mostly 0 at baseline. A logistic regression model was used to analyze the relationship between meniscus pathology, synovitis, and KOA progression. Mediation analysis was used to evaluate the mediation effect of synovitis. The average age of the participants was 61 years old, 62% of which were female. The medial meniscus extrusion was longitudinally correlated with the progression of KL (odds ratio [OR]: 2.271, 95% confidence interval [CI]: 1.412–3.694) and medial JSN (OR: 3.211, 95% CI: 2.040–5.054). Additionally, the longitudinal correlation between medial meniscus damage and progression of KOA (OR: 1.853, 95% CI: 1.177–2.941) and medial JSN (OR: 1.655, 95% CI: 1.053–2.602) was significant. Synovitis was found to mediate the relationship between medial meniscus extrusion and KL and medial JSN progression at baseline (β: 0.029, 95% CI: 0.010–0.053; β: 0.022, 95% CI: 0.005–0.046) and beyond 24 months (β: 0.039, 95% CI: 0.016–0.068; β: 0.047, 95% CI: 0.020–0.078). However, we did not find evidence of synovitis mediating the relationship between meniscal damage and KOA progression. Synovitis mediates the relationship between medial meniscus extrusion (rather than meniscus damage) and KOA progression.

Association of Dipeptidylpeptidase 4 (CD26) With Chondrocyte Senescence and Radiographic Progression in Knee Osteoarthritis.

To evaluate the association of dipeptidylpeptidase 4 (DPP-4; also known as CD26) with cellular senescence of human cartilage and progression of knee osteoarthritis (OA). Articular cartilage sections and chondrocytes were acquired from 35 individuals undergoing total knee replacement for OA to evaluate the following: 1) the association between OA severity and established senescence markers (senescence-associated β-galactosidase activity and p16), which was quantified using immunohistochemistry and flow cytometry (n=19 samples); 2) the coexpression of DPP-4 with established senescence markers, which was assessed using flow cytometry; and 3) expression levels of anabolic and catabolic genes, senescence-related genes, and senescence-associated secretory phenotypes in DPP-4+ and DPP-4- cells, which were isolated using fluorescence-activated cell sorting or magnetic-activated cell sorting (n=16 samples). The concentration of soluble DPP-4 was measured in samples of synovial fluid and samples of plasma from the Prediction of Osteoarthritis Progression cohort and then evaluated for association with the severity of radiographic knee OA at baseline (n=65 samples) and the progression of structural radiographic OA (n=57 samples) over a 3-year period. DPP-4 expression was associated with higher senescence-associated β-galactosidase activity, p16 expression, senescence-related gene and catabolic gene (ADAMTS5, MMP13, IL6, and IL8) expression, higher senescence-associated secretory phenotype secretion, and lower anabolic gene (COL2A1 and ACAN) expression in primary chondrocytes. Synovial fluid DPP-4 concentration was associated with radiographic OA progression (odds ratio 105.32; P=0.015), proteases (synovial fluid matrix metalloproteinase 1 and matrix metalloproteinase 3), aggrecan degradation (synovial fluid sulfated glycosaminoglycan), indicators of activated macrophages (synovial fluid CD14 and CD163), and inflammation (synovial fluid interleukin-6). Our study identifies DPP-4 as a key surface marker in senescent chondrocytes and a predictor of radiographic OA progression.

Radiographically detectable intra-articular mineralization: Predictor of knee osteoarthritis outcomes or only an indicator of aging? A brief report from the osteoarthritis initiative

ObjectiveTo determine the association between Intra-articular mineralization (IAM) and knee osteoarthritis (OA) outcomes stratified according to participants’ age. MethodsParticipants from the Osteoarthritis Initiative (OAI) with baseline radiographic OA (i.e., Kellgren-Lawrence grade ≥2 with Osteoarthritis Research Society International (OARSI) atlas joint space narrowing (JSN)) in either knee were identified. Both knees and dominant hand baseline radiographs were evaluated for the presence of IAM. Whole-grade OARSI-JSN radiographic progression and increased Western Ontario and McMaster universities osteoarthritis index scores of the knees with baseline radiographic OA (assessed annually) were defined as radiographic and symptomatic progression, respectively. Cox proportional-hazards and longitudinal multilevel regression models investigated radiographic and symptomatic progression, respectively. Results2010 participants with baseline radiographic OA in either one or both knees (N ​= ​2976) were identified. 178 participants had baseline IAM (hand radiographs ​= ​46, knee radiographs ​= ​166, both ​= ​34). An adjusted logistic regression model suggests an association between age and IAM (Odds Ratio: 1.06, 95% Confidence Interval (CI): 1.04–1.08). Presence of any IAM was not associated with whole-grade OARSI-JSN (Hazard Ratio (HR): 1.00, 95% CI: 0.73–1.37) or symptomatic progression (Estimated difference: 1.24, p-value: 0.13) in all participants. Using stratification analysis, in younger participants <60 years old, presence of any IAM was associated with radiographic progression (HR: 1.90, 95% CI: 1.01–3.60). ConclusionAlthough the presence of any radiographic IAM increases with higher age and does not predict knee OA outcomes across the entire sample of OAI participants, it is associated with knee OA radiographic progression in participants aged <60.

Deep learning applications in osteoarthritis imaging.

Deep learning (DL) is one of the most exciting new areas in medical imaging. This article will provide a review of current applications of DL in osteoarthritis (OA) imaging, including methods used for cartilage lesion detection, OA diagnosis, cartilage segmentation, and OA risk assessment. DL techniques have been shown to have similar diagnostic performance as human readers for detecting and grading cartilage lesions within the knee on MRI. A variety of DL methods have been developed for detecting and grading the severity of knee OA and various features of knee OA on X-rays using standardized classification systems with diagnostic performance similar to human readers. Multiple DL approaches have been described for fully automated segmentation of cartilage and other knee tissues and have achieved higher segmentation accuracy than currently used methods with substantial reductions in segmentation times. Various DL models analyzing baseline X-rays and MRI have been developed for OA risk assessment. These models have shown high diagnostic performance for predicting a wide variety of OA outcomes, including the incidence and progression of radiographic knee OA, the presence and progression of knee pain, and future total knee replacement. The preliminary results of DL applications in OA imaging have been encouraging. However, many DL techniques require further technical refinement to maximize diagnostic performance. Furthermore, the generalizability of DL approaches needs to be further investigated in prospective studies using large image datasets acquired at different institutions with different imaging hardware before they can be implemented in clinical practice and research studies.

Effusion-synovitis worsening mediates the association between body mass index and Kellgren-Lawrence progression in obese individuals: data from the Osteoarthritis Initiative

Both obesity and synovitis are independently associated with knee osteoarthritis (KOA) progression. We examined whether synovitis mediates the relationship between body mass index (BMI) and KOA radiographic progression in the Osteoarthritis Initiative (OAI) cohort. We conducted a case-control study within the OAI. Cases (n=315) were right knees with an increase of ≥1 Kellgren-Lawrence from baseline to 48 months of follow-up. Controls (n=315) were right knees with no KL change. Cases and controls were matched by age, sex, race, and baseline KL. MRI Osteoarthritis Knee Score (MOAKS) at baseline and at 2 years was used for a semi-quantitative scoring (0-3) of effusion-synovitis and Hoffa-synovitis. Conditional logistic regression estimated associations between BMI and synovitis with KOA progression. Mediation analysis was used to assess the mediating effects of synovitis. The mean age of participants was 61 years, 70.8% were women, and 87% were White. KOA progression was associated with higher BMI (adjusted OR 1.05; 95%CI 1.01-1.09) and effusion-synovitis relative to no effusion-synovitis (adjusted OR 2.2; 95%CI 1.6-3.1). Associations between effusion-synovitis worsening and KOA progression were more pronounced among obese individuals (OR 34.1; 95%CI 4.2-274.8; P=0.001) compared to normal weight (OR 3.2; 95%CI 0.8-12.8, P=0.096) individuals. Effusion-synovitis at 2 years, but not at baseline, mediated the relationship between BMI and KOA progression over a 4-year period. We found that effusion-synovitis worsening mediated the association between BMI and KOA progression and was associated with increased risk of KOA progression, particularly among obese individuals.

LONGITUDINAL CHANGE IN QUANTITATIVE 3D MEDIAL MENISCUS MEASURES PRECEDING TO AND CONCURRENT WITH STRUCTURAL KNEE OSTEOARTHRITIS PROGRESSION - DATA FROM THE OAI FNIH BIOMARKER STUDY

Purpose: The menisci of the knee joint play an important role in distributing joint loads, reducing contact stress between femorotibial cartilages, and guiding knee joint movement. Meniscal pathology such as extrusion and tears are very common and associated with incidence and progression of radiographic knee osteoarthritis (KOA). The meniscus position and integrity are also known to affect the minimum radiographic JSW (minJSW). We previously observed 3D quantitative measurements of meniscus position and morphology to be associated with subsequent structural progression, defined as both loss in radiographic minJSW and cartilage thickness and observed change in 3D quantitative meniscus measures concurrent with minJSW loss.

The association between vitamin K and medial tibial-femoral knee osteoarthritis progression: Data from the osteoarthritis initiative

ObjectiveWe sought to examine the prospective association of vitamin K with radiographic progression of knee osteoarthritis. MethodsIn OAI, 1977 participants with radiographic knee OA and having dietary data at baseline were followed up to 12, 24, 36 and 48 months. Vitamin K was assessed with a Block Brief Food Frequency Questionnaire completed at baseline. To evaluate knee OA progression, we used quantitative medial tibiofemoral joint space width (JSW) based on plain radiographs. Progression was defined by measured Joints Space Width (JSW). The generalized linear mixed model was used to test the association of vitamin K and change in JSW over time, while adjusting for baseline KL grade and other potential confounding factors. ResultsWe found a relationship between dietary Vitamin K with structural progression of knee osteoarthritis measured by quantitative JSW in a dose response manner. When stratified among KL groups, a significant trend was seen in the KL2 (p ​< ​0.025) ConclusionOur results suggest that decreased vitamin K intake from food may be associated with increased progression of knee OA. Replication of these findings in other studies validating decreased vitamin K intake leading to increased knee OA progression are needed. SignificanceThis study provides insight into a potential novel risk factor for the progression of knee OA. These findings have may have clinical implications given the potential for Vitamin K to be a simple therapy for knee OA.

Synovitis does not mediate the relationship between body mass index and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative

Purpose: Synovial inflammation is associated with knee osteoarthritis (KOA) progression. Body mass index (BMI) has also been associated with KOA progression. Yet, it is unclear whether synovial inflammation mediates the association of BMI with KOA progression. Here, we examined the mediating effect of synovitis in the association between BMI and progression of radiographic KOA in the Osteoarthritis Initiative (OAI) cohort.

Cartilage specific deletion of chemokine receptor 2 has a temporal action on joint damage during injury induced osteoarthritis

Purpose: Increased expression of chemokines in cartilage, synovial membrane and subchondral bone are believed to be linked to osteoarthritis (OA). CCR2 has been recognized as an important potential target in OA: CCR2, its ligands CCL12 (a.k.a. MCP-5) and CCL2 (a.k.a. MCP-1, the major human circulating ligand), are significantly increased in both rodent models of OA and in humans with OA. In addition, they have been shown to mediate OA pain. In previous clinical studies, we determined that CCL2 serum levels at baseline were significantly associated with radiographic knee OA progression and joint space narrowing at 5-year follow up.

The association between worsening of synovitis and radiographic osteoarthritis progression is more pronounced in obese individuals: data from the osteoarthritis initiative

Purpose: Synovial inflammation in the knee is associated with knee osteoarthritis (KOA) progression. Yet, the relation of body mass index (BMI) to worsening of synovitis and OA progression remains unknown. This study investigated the association of synovitis progression during a 2-year period with radiographic KOA progression over 48 months in 3 groups of patients according to their BMI.

Association between current medication use and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative.

ObjectiveUse of specific medications may accelerate the progression of radiographic knee OA (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA.MethodsWe used longitudinal data from the Osteoarthritis Initiative (OAI), an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (Kellgren–Lawrence grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96 months follow-up. We used random effects, panel regression to assess the association between current medication use (non-users as reference group) and change in mJSW.ResultsOf 2054 eligible participants, 2003 participants with baseline mJSW data were included [55.7% female, mean age 63.3 (s.d. 8.98) years]. Of seven medication classes, at baseline NSAIDs were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use was frequent and the following comorbidity medications were used most frequently: statins (27.4%), anti-hypertensives (up to 15.0%), anti-depressant/anxiolytics/psychotropics (14.0%), osteoporosis-related medication (10.9%) and diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = −0.042, 95% CI −0.08, −0.0004). No other associations were observed.ConclusionsIn current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.

Shortest time interval for detecting the progression of knee osteoarthritis on consecutive X-rays.

Objectives This study aims to find the shortest needed time interval between two consecutive anteroposterior (AP) knee X-rays of the same patient to determine the progression of knee osteoarthritis (KOA) by a trained eye. Patients and methods In this retrospective study, 2,145 AP knee X-rays of 848 primary KOA patients (331 males, 517 females; mean age 65±9 years; range, 50 to 92 years) followed-up between January 2014 and December 2017 were used. Randomly generated 1,280 pairs of knee X-rays were shown to 14 orthopedic surgeons working in the Department of Orthopedics and Traumatology, and then the physicians were asked to select the second X-ray of the same arthritis knee. The physicians completed the test twice. The patient's age, gender, time interval between two radiographs and the responses of the physicians were recorded. Results Our results showed that if the time interval between the two radiographs was six months or more, the correct estimation rates increased gradually. When the time interval was 36 months and more, the ratio reached 92%. The sensitivity and specificity rate of the method was 81%, while the positive predictive value was 86%. However, interestingly, age or gender did not have any effect on this result. Conclusion In our study, X-rays taken in less than six months apart could not give additional information about the radiographic progression of KOA. To discern between the progression of KOA, we recommend that there be a 12 to 18-month interval between consecutive X-rays. The data of our study can be used for a routine algorithm to be developed for the evaluation of KOA patients.

Synergistic Roles of Macrophages and Neutrophils in Osteoarthritis Progression.

To evaluate the role of immune cells and their effector cytokines in the pathogenesis and progression of knee osteoarthritis (OA) in matched OA synovial fluid (SF) and synovial tissue samples. Cells from matched samples of synovial tissue and SF acquired from individuals undergoing total knee replacement for OA (n = 39) were characterized for immune cell-associated surface markers and intracellular cytokine expression using polychromatic flow cytometry. Additional individuals with radiographic knee OA (Kellgren/Lawrence severity grades ≥1) who had available etarfolatide (inflammatory cell) imaging (n = 26) or baseline and 3-year data on progression of radiographic knee OA (n = 85) were also assessed. SF cytokine concentrations in all cohorts were evaluated for associations with synovial tissue and SF cell phenotypes and severity of radiographic knee OA. Macrophages (predominant in the synovial tissue, 53% of total cells) and neutrophils (predominant in the SF, 26% of total cells) were the major immune cell populations identified in the OA knee joints, exhibiting expression of or association with transforming growth factor β1 (TGFβ1) and elastase, respectively, in the SF. Expression levels of TGFβ1 and elastase were significantly associated with severity of radiographic knee OA. Baseline SF concentrations of TGFβ1 and elastase along with radiographic knee OA severity scores were predictive of knee OA progression, with areas under the receiver operating characteristic curves of 0.810 (for TGFβ1), 0.806 (for elastase), and 0.846 (for both TGFβ1 and elastase combined), with greater stability of prediction when both markers were utilized. Our findings demonstrate the hitherto underappreciated role of neutrophils in the sterile inflammatory process and progression of OA. Two soluble mediators, SF elastase and TGFβ1, are strong predictors of knee OA progression, reflecting a synergistic role of neutrophil and macrophage populations in the pathogenesis and worsening of OA that could potentially be utilized to identify patients who may have a greater risk of more rapid disease progression.

The combination of an inflammatory peripheral blood gene expression and imaging biomarkers enhance prediction of radiographic progression in knee osteoarthritis

ObjectivePredictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone.MethodsPBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC).ResultsWe validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p < 0.0001) and the odds ratio from 6.31 to 19.10 (p < 0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL inflammatory gene expression further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL inflammatory gene expression and BML independently influenced mJSN.ConclusionThe use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

Arthroscopic partial meniscectomy for a degenerative meniscus tear: a 5 year follow-up of the placebo-surgery controlled FIDELITY (Finnish Degenerative Meniscus Lesion Study) trial

ObjectivesTo assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up.DesignMulticentre, randomised, participant- and...

Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative.

Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today's more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m2 ) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non-bisphosphonate users and followed until first radiographic knee OA progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard ratios (HRs) between bisphosphonate users versus nonusers, with an interaction term for baseline KL grade (KL <2 or KL ≥2). We identified 1977 eligible women (n = 346 bisphosphonate users). Propensity-matched results indicated that bisphosphonate users with KL grade <2 were protected against progression (HRKL<2 0.53; 95% CI, 0.35 to 0.79), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥2 (HRKL≥2 1.06; 95% CI, 0.83 to 1.35). When restricting analyses to those with BMI <25 kg/m2 , effects were strengthened (HRKL<2 0.49 [95% CI, 0.26 to 0.92]; HRKL≥2 0.69 [95% CI, 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. © 2020 American Society for Bone and Mineral Research (ASBMR).

Phenylalanine Is a Novel Marker for Radiographic Knee Osteoarthritis Progression: The MOST Study.

To identify plasma markers associated with an increased risk of radiographic knee osteoarthritis(OA) progression using a metabolomics approach. Study participants were from the Multicenter Osteoarthritis Study (MOST) and were categorized into 2 groups based on the presence of baseline radiographic OA. Subjects in group 1 had unilateral knee OA and subjects in group 2 had bilateral knee OA. Progression was defined as a half-grade or greater worsening in joint space width at 30-month follow-up. For group 1, a participant progressed when their OA knee showed radiographic progression and the contralateral knee developed OA; for group 2, a participant progressed when both knees with OA showed radiographic progression. Metabolomic profiling was performed on plasma samples collected at baseline and logistic regression was performed to test the association between each metabolite and knee OA progression after adjustment for age, sex, BMI, and clinic site. Significance was defined as P ≤ 0.0003 in the combined analysis. There were 234 progressors (57 in group 1 and 177 in group 2) and 322 nonprogressors (206 in group 1 and 116 in group 2) included in the analyses. Among 157 metabolites studied, we found that odds of progression were 1.46 times higher per SD increase of phenylalanine level (95% CI 1.20-1.77, P = 0.0001) in the combined analysis. Sex-specific analysis showed that an association was seen in women (P = 0.0002) but not in men. Our data suggest that phenylalanine might be a novel plasma marker for higher risk of bilateral radiographic knee OA progression in women.

The correlation of dairy products and radiographic progression of knee osteoarthritis of Tibetan in plateau region

Purpose: Knee osteoarthritis (KOA) is the most common joint disease targeting articular cartilage which leads to dysfunction and disabilities. Radiography is the gold standard for diagnosing OA using the Kellgren-Lawrence(KL) grading system. We have found that the prevalence of KOA was higher in plateau region of China , until now, there are no such studies concerning the risk factors of radiographic progression of KOA of inhabitants in plateau region. Therefore, our aim was to investigate the risk factors of radiographic progression of KOA patients of Tibetan in plateau region.

Radiographic hand osteoarthritis and worsening of mri-based tibiofemoral osteoarthritis-related structural damage, data from the OAI study

Purpose: To determine whether the presence of hand osteoarthritis (OA) is associated with radiographic knee OA progression (over 48-months) and MRI-based knee OA structural damage worsening (over 24-months). Methods: 600 subjects from the Foundation for the National Institute of Health (FNIH) project which is an IRB approved HIPAA compliant study were included (one index knee and hand in each subject). Baseline hand radiography of all subjects was measured for the presence of hand OA. PA radiographs of the dominant hand or the left hand (in case of ambidexterity) of included subjects were assessed by a musculoskeletal radiologist in a blinded fashion. Distal interphalangeal (DIP), proximal interphalangeal (PIP), interphalangeal (IP), metacarpophalangeal (MCP), and the first carpometacarpal (CMC) joints were assessed for the presence of OA (modified Kellgren and Lawrence (mKL) grade >=2) in each hand joint. Baseline and follow-up knee radiographic measurements and MRI OA Knee Score (MOAKS) variables for cartilage damage, bone marrow lesions, osteophytes, effusion, and Hoffa-synovitis as well as MRI-based knee periarticular bone area measurements were extracted. The association between the presence of hand OA (presence vs. absence of hand OA in each hand joint) and 48-months radiographic knee OA progression (defined as >0.7mm reduction in medial tibiofemoral joint space width) as well as 24-months change in knee MOAKS and periarticular bone measurements were analyzed using regression model (adjusted for age and sex). Results: Presence of any carpometacarpal (CMC) OA (OR 95%CI: 1.58(0.96-2.62)) and overall hand OA (prsence of any mKL>=2 in all hand joints) (OR 95%CI: 1.44(0.97-2.07)) was associated increased odds for being a radiographic or composite progressor (approached but not reached significance). In comparison with controls, subjects with hand OA showed higher odds of worsening tibial/femoral cartilage damage (OR 95%CI: 1.38(0.95-2.01) and 1.79(1.24-2.58)) and femoral periarticular bone area expansion (Beta 95%CI: 10.54(1.40-19.69)) over 24-months. CMC OA and 24-months worsening of MRI-based tibiofemoral cartilage damage and periarticular bone area expansion were also showed approached significant associations. Conclusions: Presence of hand OA, especially in CMC joint, is associated with longitudinal MRI-based knee OA-related structural damage worsening including tibial/femoral cartilage damage and periarticular bone area expansion.

In-vivo inducible tissue-specific deletion of chemokine receptor-2 in mouse cartilage decreases joint damage during injury-induced osteoarthritis

Purpose: Increased expression of chemokines in cartilage, synovial membrane and subchondral bone are believed to be linked to osteoarthritis (OA). CCR2 has been recognized as an important potential target in OA: CCR2, its ligands CCL12 (a.k.a. MCP-5) and CCL2 (a.k.a. MCP-1, the major human circulating ligand), are significantly increased in both rodent models of OA and in humans with OA. In addition, they have been shown to mediate OA pain. In previous clinical studies, we determined that CCL2 serum levels at baseline were significantly associated with radiographic knee OA progression and joint space narrowing at 5-year follow up. Using the destabilization of medial meniscus (DMM) murine model of injury-induced OA, we demonstrated that targeting the CCR2 signaling at early OA stages had beneficial effects on OA progression and that there was a disconnect between structure and pain that has been noted in human OA. We therefore hypothesize that alterations in joint mechanics upregulate the CCR2 pathway in cartilage and bone in a time-dependent manner altering the structural organization of both tissues, ultimately leading to OA and pain. In the present study, by using a temporal and tissue specific inactivation of CCR2 in cartilage, we determine the role of CCR2 signaling in-vivo at sequential times during injury-induced OA in order to establish the contribution of CCR2 to the development of whole joint degeneration. Methods: We obtained an inducible tissue-specific CCR2 deletion in chondrocytes by combining chondrocyte-specific expression of CreER with Tamoxifen (Tam) injections in CCR2flx/flxeGFP mice crossed with Aggrecan-CreERT2 (CCR2AggERKO). The Cre-mediated recombination deletes CCR2 exon3, generating a functional knockout, and activates the expression of eGFP under the CCR2 locus. Therefore, recombination can be validated by GFP expression. CCR2AggERKO and CCR2flx/flx mice were injected with Tamoxifen (40μg/g) for 5 days and subjected to DMM 1 week after the last injection. Mice were euthanized at 2, 4, 8 and 12 weeks after DMM and knees were prepared for histological evaluation (Safranin-O/Fast Green, H&E) and immunohistochemical (IHC) analyses with anti-GFP, anti-Collagen10 and anti-osterix antibodies). Results: We successfully inactivated the CCR2 receptor in the cartilage tissue, as shown by the intense GFP expression in the cartilage tissues of CCR2AggERKO mice compared to controls. The expression of CCR2 in other tissues is not altered by the recombination. Histological evaluation shows that deletion of CCR2 in cartilage tissue decreases articular cartilage structure score and Safranin-O staining score at 4, 8 and 12 weeks post-surgery compared to controls. In addition, at both 8 and 12 weeks post surgery, protein levels of Collagen 10 are significantly higher in DMM-CCR2AggERKO mice while almost absent in DMM-controls, were the whole cartilage is replaced by bone. Conclusions: Our results show that we were able to selectively inhibit the CCR2 expression in chondrocytes during OA progression, while its expression was unchanged in other joint tissues. We demonstrated that the CCR2 deletion in cartilage slows cartilage damage at the mild, moderate and severe OA stage compared to controls. Other studies are currently in progress in our lab to determine whether CCR2 deletion in cartilage indirectly affect the bone tissue as well. Behavioral pain analyses are also in progress to determine whether CCR2 cartilage deletion alleviate pain responses.