PubMed · 14815208
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V G von MUNDY. 1951-01-26. [Rheumatism problem].. https://pubmed.ncbi.nlm.nih.gov/14815208/
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Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK-ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK-ligand/OPG pathway, and the clinical development of anti-RANK-ligand therapy.
PURPOSE OF REVIEW: In this review we summarize some of the most recent research in the area of local bone regeneration. These innovations may be relevant in the orthopaedic treatment of patients with rheumatoid arthritis, or other inflammatory arthridities, as such patients often present with inadequate bone stock. RECENT FINDINGS: Bone grafting remains the standard treatment for bone deficiency. Several new approaches, such as the use of concentrated blood products or osteoprogenitor cells in conjunction with grafts, have been developed but remain to be tested clinically. Experimental studies have elucidated important aspects of the biology of bone graft remodeling and osteoprogenitor cell differentiation. Materials that can serve as graft alternatives continue to be developed. Positive experimental findings have resulted from combinations of such materials with osteoprogenitor cells or osteoinductive factors such as bone morphogenetic proteins. SUMMARY: While few studies to date have examined the specific use of these new strategies in the setting of rheumatoid arthritis, many hold promise for patients with rheumatoid arthritis and other inflammatory and metabolic conditions that affect bone quality and quantity.
Human HtrA1 belongs to a widely conserved family of serine proteases involved in various aspects of protein quality control and cell fate. Although HtrA1 has been implicated in the pathology of several diseases, its precise biological functions remain to be established. Through identification of potential HtrA1 targets, studies presented herein propose that within the context of arthritis pathology HtrA1 contributes to cartilage degradation. Elevated synovial HtrA1 levels were detected in fluids obtained from rheumatoid and osteoarthritis patients, with synovial fibroblasts identified as a major source of secreted HtrA1. Mass spectrometry analysis of potential HtrA1 substrates within synovial fluids identified fibronectin as a candidate target, and treatment of fibronectin with recombinant HtrA1 led to the generation of fibronectin-degradation products that may be involved in cartilage catabolism. Consistently, treatment of synovial fibroblasts with HtrA1 or HtrA1-generated fibronectin fragments resulted in the specific induction of matrix metalloprotease 1 and matrix metalloprotease 3 expression, suggesting that HtrA1 contributes to the destruction of extracellular matrix through both direct and indirect mechanisms.