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Abstract Background Several symptom-relieving interventions have been shown to be efficacious among osteoarthritis (OA) patients with knee effusion; however, not every symptomatic knee OA patient has clinical effusion. Results may be over-generalized since it is unclear if effused knees represent a unique pathological condition or subset compared to knees without effusion. The primary purpose of this study was to determine if biochemical differences existed between OA knees with and without effusion. Methods The present cross-sectional study consisted of 22 volunteers (11 with knee effusion, 11 without knee effusion) with confirmed late-stage radiographic knee OA (Kellgren-Lawrence score ≥ 3). Synovial fluid samples were collected and analyzed using a custom multiplex enzyme-linked immunosorbent assay to determine eight specific biomarker concentrations (e.g., catabolic, anabolic). Results Matrix metalloproteinase (MMP)-3, tissue inhibitor of MMPs (TIMP)-1, TIMP-2, and interleukin-10 were significantly higher in the knees with effusion than in the knees without effusion. Conclusions The biochemical differences that existed between knees with and without effusion provide support that OA subsets may exist, characterized by distinct biochemical characteristics and clinical findings (e.g., effusion).

Abstract Background We previously reported early tissue injury, increased serum and tissue inflammatory cytokines and decreased grip in young rats performing a moderate demand repetitive task. The tissue cytokine response was transient, the serum response and decreased grip were still evident by 8 weeks. Thus, here, we examined their levels at 12 weeks in young rats. Since aging is known to enhance serum cytokine levels, we also examined aged rats. Methods Aged and young rats, 14 mo and 2.5 mo of age at onset, respectfully, were trained 15 min/day for 4 weeks, and then performed a high repetition, low force (HRLF) reaching and grasping task for 2 hours/day, for 12 weeks. Serum was assayed for 6 cytokines: IL-1alpha, IL-6, IFN-gamma, TNF-alpha, MIP2, IL-10. Grip strength was assayed, since we have previously shown an inverse correlation between grip strength and serum inflammatory cytokines. Results were compared to naïve (grip), and normal, food-restricted and trained-only controls. Results Serum cytokines were higher overall in aged than young rats, with increases in IL-1alpha, IFN-gamma and IL-6 in aged Trained and 12-week HRLF rats, compared to young Trained and HRLF rats (p < 0.05 and p < 0.001, respectively, each). IL-6 was also increased in aged 12-week HRLF versus aged normal controls (p < 0.05). Serum IFN-gamma and MIP2 levels were also increased in young 6-week HRLF rats, but no cytokines were above baseline levels in young 12-week HRLF rats. Grip strength declined in both young and aged 12-week HRLF rats, compared to naïve and normal controls (p < 0.05 each), but these declines correlated only with IL-6 levels in aged rats (r = -0.39). Conclusion Aging enhanced a serum cytokine response in general, a response that was even greater with repetitive task performance. Grip strength was adversely affected by task performance in both age groups, but was apparently influenced by factors other than serum cytokine levels in young rats.

To examine the chronic effect of force on mRNA and protein expression levels of fibrosis-related genes in flexor digitorum muscles in a rat model of repetitive overuse injury that induces muscle fibrosis at high force levels. Two groups of rats were trained to perform a voluntary repetitive lever-pulling task at either a high (HFHR) or a low force (LFHR) for 18 weeks, while a control group (FRC) performed no task. RNA and protein were prepared from forelimb flexor digitorum muscles. Fibrosis-related gene RNA transcripts were evaluated using quantitative PCR (qPCR) and analyzed using the geometric mean of three housekeeping genes or the mean of each individually as reference. Protein levels were quantified using ELISA, western blot, or immunohistofluorescence. Of eight fibrosis-related mRNAs examined, only FGF2 demonstrated a consistent significant increase in the HFHR group, compared to the FRC group. However, protein amounts of collagen type 1, collagen type 3, and TGFβ1 were significantly higher in the HFHR, compared to the FRC and LFHR groups, while CCN2 and FGF2 were higher in both HFHR and LFHR, compared to the FRC group. Our results suggest that there is steady-state transcription of fibrogenic genes in muscles with established fibrosis, implying that post-transcriptional processes are responsible for the increased protein levels of fibrotic factors during muscle overuse conditions. We hypothesize that targeting such pathways represents a valid approach to treat overuse injury. Alternatively, FGF2 gene expression may represent a valid target for therapy. [ABSTRACT FROM AUTHOR]

Purpose/Aim: We recently found that blocking CCN2 signaling using a monoclonal antibody (FG-3019) may be a novel therapeutic strategy for reducing overuse-induced tissue fibrosis. Since CCN2 plays roles in osteoclastogenesis, and persistent performance of a high repetition high force (HRHF) lever pulling task results in a loss in trabecular bone volume in the radius, we examined here whether blocking CCN2 signaling would reduce the early catabolic effects of performing a HRHF task for 3 weeks. Materials and Methods: Young adult, female, Sprague-Dawley rats were operantly shaped to learn to pull at high force levels, before performing the HRHF task for 3 weeks. HRHF task rats were then left untreated (HRHF Untreated), treated in task weeks 2 and 3 with a monoclonal antibody that antagonizes CCN2 (HRHF+FG-3019), or treated with an IgG (HRHF+IgG), while continuing to perform the task. Non-task control rats were left untreated. Results: In metaphyseal trabeculae of the distal radius, HRHF Untreated and HRHF-IgG rats showed increased osteoblast numbers and other indices of bone formation, compared to controls, yet decreased trabecular bone volume, increased osteoclast numbers, and increased serum CTX-1 (a serum biomarker of bone resorption). HRHF+FG-3019 rats also showed increased osteoblast numbers and bone formation, but in contrast to HRHF Untreated and HRHF-IgG rats, showed higher trabecular bone volume, and reduced osteoclast numbers and serum CTX-1 levels (and statistically similar to Control levels). Conclusions: HRHF loading increased bone formation in each task group, yet blocking CCN2 dampened trabecular bone catabolism by reducing osteoclast numbers and activity. [ABSTRACT FROM AUTHOR]

Context: Joint trauma is a risk factor for osteoarthritis (OA), which is becoming an increasingly important orthopedic concern for athletes and nonathletes alike. For advances in OA prevention, diagnosis, and treatment to occur, a greater understanding of the biochemical environment of the affected joint is needed. Objective: To demonstrate the potential of a biochemical technique to enhance our understanding of and diagnostic capabilities for osteoarthritis. Design: Cross-sectional. Setting: Outpatient orthopedic practice. Participants: 8 subjects: 4 OA-knee participants (65 ± 6 y of age) and 4 normal-knee participants (54 ± 10 y) with no history of knee OA based on bilateral standing radiographs. Intervention: The independent variable was group (OA knee, normal knee). Main Outcome Measures: 16 knee synovial-protein concentrations categorized as follows: 4 as pro-inflammatory, or catabolic, cytokines; 5 as anti-inflammatory, or protective, cytokines; 3 as catabolic enzymes; 2 as tissue inhibitors of metalloproteinases [TIMPs]; and 2 as adipokines. Results: Two anti-inflammatory cytokines (interleukin [IL]-13 and osteoprotegerin) and a pro-inflammatory cytokine (IL-1ß) were significantly lower in the OA knees. Two catabolic enzymes (matrix metalloproteinase [MMP]-2 and MMP-3) were significantly elevated in OA knees. TIMP-2, an inhibitor of MMPs, was significantly elevated in OA knees. Conclusions: Six of the 16 synovial-fluid proteins were significantly different between OA knees and normal knees in this study. Future research using a similar multiplex ELISA approach or other proteomic techniques may enable researchers and clinicians to develop more accurate biochemical profiles of synovial fluid to help diagnose OA, identify subsets of OA or individual characteristics, guide clinical decisions, and identify patients at risk for OA after knee injury. [ABSTRACT FROM AUTHOR]

1. Introduction Work-related upper limb disorders in the United States are estimated to cost over $61.2 billion annually. In 2006, the number of occupational injuries involving days away from work [...], We used our voluntary rat model of reaching and grasping to study the effect of performing a high-repetition and high- force (HRHF) task for 12 weeks on wrist joints. We also studied the effectiveness of ibuprofen, administered in the last 8 weeks, in attenuating HRHF-induced changes in these joints. With HRHF task performance, ED1+ and COX2+ cells were present in subchondral radius, carpal bones and synovium; IL-1alpha and TNF-alpha increased in distal radius/ulna/carpal bones; chondrocytes stained with Terminal deoxynucleotidyl Transferase- (TDT-) mediated dUTP-biotin nick end-labeling (TUNEL) increased in wrist articular cartilages; superficial structural changes (e.g., pannus) and reduced proteoglycan staining were observed in wrist articular cartilages. These changes were not present in normal controls or ibuprofen treated rats, although IL-1alpha was increased in reach limbs of trained controls. HRHF-induced increases in serum C1,2C (a biomarker of collagen I and II degradation), and the ratio of collagen degradation to synthesis (C1,2C/CPII; the latter a biomarker of collage type II synthesis) were also attenuated by ibuprofen. Thus, ibuprofen treatment was effective in attenuating HRHF-induced inflammation and early articular cartilage degeneration.