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Abstract Objectives Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation in multiple articular joints, causing pain, joint damage, and loss of joint function. Despite the successful development of disease-modifying therapies, the heterogeneity of RA means that a significant proportion of patients respond poorly to treatment. This highlights the need for personalized medicine and predictive biomarkers to optimize treatment efficacy, safety, and cost. This study aimed to explore the relationship between type VI collagen (Col VI) remodeling and clinical response to anti-IL-6 receptor treatment. Methods Type VI collagen degradation was quantified using the C6M biomarker, a fragment of type VI collagen degraded by MMPs. Longitudinal differences in average biomarker levels between placebo and treatment groups were estimated using linear mixed models. The predictive capacity of the marker based on change from baseline to 4 weeks was analyzed using logistic regression. Results Both 4 mg and 8 mg doses of Tocilizumab (TCZ) reduced serum C6M concentrations compared to the placebo. Furthermore, C6M levels were more reduced in patients responding to treatment compared to early non-responders. A lower early reduction in C6M was associated with reduced odds of ACR treatment response and lowered disease activity. Conclusion These findings suggest that quantifying type VI collagen turnover may aid in identifying patients less likely to respond to treatment, indicating a new path towards optimizing patient care. Further studies are needed to validate these findings and explore the underlying mechanisms driving the observed relationships.

Abstract Objectives To investigate cartilage tissue turnover in response to a supervised 12-week exercise-related joint loading training program followed by a 6-month period of unsupervised training in patients with knee osteoarthritis (OA). To study the difference in cartilage tissue turnover between high- and low-resistance training. Method Patients with knee OA were randomized into either high-intensity or low-intensity resistance supervised training (two sessions per week) for 3 months and unsupervised training for 6 months. Blood samples were collected before and after the supervised training period and after the follow-up period. Biomarkers huARGS, C2M, and PRO-C2, quantifying cartilage tissue turnover, were measured by ELISA. Changes in biomarker levels over time within and between groups were analyzed using linear mixed models with baseline values as covariates. Results huARGS and C2M levels increased after training and at follow-up in both low- and high-intensity exercise groups. No changes were found in PRO-C2. The huARGS level in the high-intensity resistance training group increased significantly compared to the low-intensity resistance training group after resistance training (p = 0.029) and at follow-up (p = 0.003). Conclusion Cartilage tissue turnover and cartilage degradation appear to increase in response to a 3-month exercise-related joint loading training program and at 6-month follow-up, with no evident difference in type II collagen formation. Aggrecan remodeling increased more with high-intensity resistance training than with low-intensity exercise. These exploratory biomarker results, indicating more cartilage degeneration in the high-intensity group, in combination with no clinical outcome differences of the VIDEX study, may argue against high-intensity training.

Abstract Osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, all have one clear common denominator; an altered turnover of bone. However, this may be more complex than a simple change in bone matrix and mineral turnover. While these diseases share a common tissue axis, their manifestations in the area of pathology are highly diverse, ranging from sclerosis to erosion of bone in different regions. The management of these diseases will benefit from a deeper understanding of the local versus systemic effects, the relation to the equilibrium of the bone balance (i.e., bone formation versus bone resorption), and the physiological and pathophysiological phenotypes of the cells involved (e.g., osteoblasts, osteoclasts, osteocytes and chondrocytes). For example, the process of endochondral bone formation in chondrocytes occurs exists during skeletal development and healthy conditions, but also in pathological conditions. This review focuses on the complex molecular and cellular taxonomy of bone in the context of rheumatological diseases that alter bone matrix composition and maintenance, giving rise to different bone turnover phenotypes, and how biomarkers (biochemical markers) can be applied to potentially describe specific bone phenotypic tissue profiles.

Abstract Background Tissue released blood-based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo-controlled study of baricitinib in patients with active rheumatoid arthritis (RA). Methods Serum biomarkers associated with synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), bone resorption (CTX-I), and bone formation (osteocalcin) were analyzed at baseline, and weeks 4 and 12, from a subgroup of patients (n = 240) randomized to placebo or 2-mg or 4-mg baricitinib (RA-BUILD, NCT01721057). Mixed-model repeated measure was used to identify biomarkers altered by baricitinib. The relationship between changes in biomarkers and clinical measures was evaluated using correlation analysis. Results Treatment arms were well balanced for baseline biomarkers, demographics, and disease activity. At week 4, baricitinib 4-mg significantly reduced C1M from baseline by 21% compared to placebo (p

Abstract Background Pain is a debilitating symptom of rheumatoid arthritis (RA), caused by joint inflammation and cartilage and bone destruction. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation in RA, but are not disease-modifying and do not prevent joint destruction when administered alone. KBPs (Key Bioscience peptides) are synthetic peptides based on salmon calcitonin and are expected to inhibit bone resorption and to be chondroprotective. In this study, we investigated if combining a standard of care NSAID (naproxen) with a KBP resulted in improvement in pain scores, as well as disease activity and structural damage in a rat model of RA. Methods Collagen-induced arthritis (CIA) was induced in 40 female Lewis rats by immunization with porcine type II collagen; 10 rats were given sham injections. CIA rats were treated with KBP and/or naproxen. Health scores and joint scores were evaluated daily. Mechanical and cold allodynia tests and burrowing tests were used to assess pain-like behaviors. Blood samples were collected for biomarker testing, and paws were collected for histology and microcomputed tomography. Results Naproxen monotherapy increased the time until humane endpoints was reached, and improved health score, pain assessments, and trabecular thickness, while KBP monotherapy did not result in improvements. Combination therapy had improved efficacy over naproxen monotherapy; combination therapy resulted in improved health scores, and importantly reduced mechanical and cold allodynia assessment. Furthermore, protection of articular cartilage structure and preservation of bone structure and bone volume were also observed. Conclusions This study demonstrates that combining KBP and naproxen may be a relevant therapeutic strategy for RA, resulting in improvements to the overall health, pain, inflammation, and joint structure.

Abstract Background Osteoclasts have been strongly implicated in osteoarthritic cartilage degradation, at least indirectly via bone resorption, and have been shown to degrade cartilage in vitro. The osteoclast resorption processes required to degrade subchondral bone and cartilage—the remodeling of which is important in the osteoarthritic disease process—have not been previously described, although cathepsin K has been indicated to participate. In this study we profile osteoclast-mediated degradation of bovine knee joint compartments in a novel in vitro model using biomarkers of extracellular matrix (ECM) degradation to assess the potential of osteoclast-derived resorption processes to degrade different knee joint compartments. Methods Mature human osteoclasts were cultured on ECMs isolated from bovine knees—articular cartilage, cortical bone, and osteochondral junction ECM (a subchondral bone-calcified cartilage mixture)—in the presence of inhibitors: the cystein protease inhibitor E-64, the matrix metalloproteinase (MMP) inhibitor GM6001, or the vacuolar-type H+-ATPase (V-ATPase) inhibitor diphyllin. Biomarkers of bone (calcium and C-terminal type I collagen (CTX-I)) and cartilage (C2M) degradation were measured in the culture supernatants. Cultures without osteoclasts were used as background samples. Background-subtracted biomarker levels were normalized to the vehicle condition and were analyzed using analysis of variance with Tukey or Dunnett’s T3 post hoc test, as applicable. Results Osteochondral CTX-I release was inhibited by E-64 (19% of vehicle, p = 0.0008), GM6001 (51% of vehicle, p = 0.013), and E-64/GM6001 combined (4% of vehicle, p = 0.0007)—similarly to bone CTX-I release. Diphyllin also inhibited osteochondral CTX-I release (48% of vehicle, p = 0.014), albeit less than on bone (4% of vehicle, p