We demonstrate the direct involvement of increased collagenase activity in the cleavage of type II collagen in osteoarthritic human femoral condylar cartilage by developing and using antibodies reactive to carboxy-terminal (COL2-3/ 4C short ) and amino-terminal (COL2-1/4N1) neoepitopes generated by cleavage of native human type II collagen by collagenase matrix metalloproteinase (MMP)-1 (collagenase-1), MMP-8 (collagenase-2), and MMP-13 (collagenase-3). A secondary cleavage followed the initial cleavage produced by these recombinant collagenases. This generated neoepitope COL2-1/4N2. There was significantly more COL2-3/ 4C short neoepitope in osteoarthritis (OA) compared to adult nonarthritic cartilages as determined by immunoassay of cartilage extracts. A synthetic preferential inhibitor of MMP-13 significantly reduced the unstimulated release in culture of neoepitope COL2-3/4C short from human osteoarthritic cartilage explants. These data suggest that collagenase(s) produced by chondrocytes is (are) involved in the cleavage and denaturation of type II collagen in articular cartilage, that this is increased in OA, and that MMP-13 may play a significant role in this process. ( J. Clin. Invest. 1997. 99:1534-1545.)

The adipokine resistin is suggested to be an important link between obesity and insulin resistance. In the present study, we assessed the impact of resistin as inflammatogenic cytokine in the setting of arthritis. In vitro experiments on human PBMC were performed to assess cytokine response and transcription pathways of resistin-induced inflammation. Proinflammatory properties of resistin were evaluated in animal model by intra-articular injection of resistin followed by histological evaluation of the joint. Levels of resistin were assessed by ELISA in 74 paired blood and synovial fluid samples of patients with rheumatoid arthritis. Results were compared with the control group comprised blood samples from 34 healthy individuals and 21 synovial fluids from patients with noninflammatory joint diseases. We now show that resistin displays potent proinflammatory properties by 1) strongly up-regulating IL-6 and TNF-α, 2) responding to TNF-α challenge, 3) enhancing its own activity by a positive feedback, and finally 4) inducing arthritis when injected into healthy mouse joints. Proinflammatory properties of resistin were abrogated by NF-κB inhibitor indicating the importance of NF-κB signaling pathway for resistin-induced inflammation. Resistin is also shown to specifically accumulate in the inflamed joints of patients with rheumatoid arthritis and its levels correlate with other markers of inflammation. Our results indicate that resistin is a new and important member of the cytokine family with potent regulatory functions. Importantly, the identified properties of resistin make it a novel and interesting therapeutic target in chronic inflammatory diseases such as rheumatoid arthritis.

The study had a favorable long-term outcome regarding incidence of radiographic knee OA, knee function and symptoms, and need for ACL reconstruction. Although risk factors for posttraumatic OA are multifactorial, the primary risk factor that stood out in this study was if a meniscectomy had been performed. Early activity modification and neuromuscular knee rehabilitation might also have been related to the low prevalence of radiographic knee OA. In patients with ACL injury willing to moderate activity level to avoid reinjury, initial treatment without ACL reconstruction should be considered.

The degree of cartilage changes by arthroscopic and radiologic examination was evaluated in a retrospective, cross-sectional study of 1012 patients with knee complaints at different times after knee injury. Patients were classified by age, sex, trauma date and type of injury. The condition of the cartilage was graded on a 1-10 scale based on findings at arthroscopy and on weight-bearing radiographs. Patients with injury to the anterior cruciate ligament (isolated or combined with injury to meniscus or collateral ligaments) showed the first radiologic signs (joint space narrowing) of osteoarthritis (OA) at an average age of about 40 years, while patients with isolated meniscus injury had the same stage of disease at an average age of about 50 years. Both study groups displayed the first radiologic signs of OA on average about 10 years after the injury and showed increasingly serious arthroscopic and radiologic signs of joint damage with increased time between injury and examination. For patients who sustained an isolated meniscus injury between the ages of 17 and 30, the average time until development of radiologic signs of OA was about 15 years, while for those who had the same injury over the age of 30, the corresponding time interval was only about 5 years. We conclude from this that knee OA becomes increasingly severe with increased time between joint injury and examination. OA changes appear sooner in older patients with knee injury than in the young.

Objective. To evaluate the effects of moderate exercise on glycosaminoglycan (GAG) content in knee cartilage in subjects at high risk of knee osteoarthritis (OA).Methods. Forty-five subjects (16 women, mean age 46 years, mean body mass index 26.6 kg/m2 ) who underwent partial medial meniscus resection 3-5 years previously were randomized to undergo a regimen of supervised exercise 3 times weekly for 4 months or to a nonintervention control group. Cartilage GAG content, an important aspect of the biomechanical properties of cartilage, was estimated by delayed gadoliniumenhanced magnetic resonance imaging of cartilage (dGEMRIC), with results expressed as the change in the T1 relaxation time in the presence of Gd-DTPA (T1[Gd]).Results. Thirty of 45 patients were examined by dGEMRIC at baseline and followup. The exercise group (n ‫؍‬ 16) showed an improvement in the T1(Gd) compared with the control group (n ‫؍‬ 14) (15 msec versus ؊15 msec; P ‫؍‬ 0.036). To study the dose response, change in the T1(Gd) was assessed for correlation with self-reported change in physical activity level, and a strong correlation was found in the exercise group (n ‫؍‬ 16, r S ‫؍‬ 0.70, 95% confidence interval [95% CI] 0.31-0.89) and in the pooled group of all subjects (n ‫؍‬ 30, r S ‫؍‬ 0.74, 95% CI 0.52-0.87).Conclusion. This in vivo cartilage monitoring study in patients at risk of knee OA who begin exercising indicates that adult human articular cartilage has a potential to adapt to loading change. Moderate exercise may be a good treatment not only to improve joint symptoms and function, but also to improve the knee cartilage GAG content in patients at high risk of developing OA.