Rheumatoid Arthritis: Walsh NC

Walsh NC, Crotti TN, Goldring SR, Gravallese EM. · Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA 02115, USA. · Immunol Rev. · Pubmed #16313352 No free full text.

Abstract: Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.

Walsh NC, Gravallese EM. · Division of Rheumatology and Metabolic Bone Disease, Beth Israel Deaconess Medical Center and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. · Curr Opin Rheumatol. · Pubmed #15201606 No free full text.

Abstract: PURPOSE OF REVIEW: Focal bone loss in inflammatory arthritis begins early in the disease process and can contribute to patient morbidity. Current treatment strategies primarily target suppression of the inflammatory cascade with varying success in limiting the progression of focal bone destruction. This review outlines the current understanding of the mechanisms mediating inflammation-induced focal bone loss in rheumatoid arthritis and other inflammatory arthritides and highlights recent studies in animal models of arthritis that have contributed to our knowledge of this process. RECENT FINDINGS: Bone-resorbing osteoclasts have been identified as important effector cells in inflammation-induced bone loss in both experimental animal models and human rheumatoid arthritis and psoriatic arthritis. The RANK/RANKL (receptor activator of nuclear factor-kappaB and RANK ligand) pathway has been shown to be essential for osteoclast differentiation in inflammatory arthritis. In addition, in vitro and in vivo studies have demonstrated that many cytokines and growth factors elaborated by inflamed synovial tissues may contribute to osteoclast differentiation and activation. SUMMARY: Elucidation of the mechanisms mediating osteoclast differentiation and function has identified new pathways for potential targeted therapeutic intervention for focal bone loss in inflammatory arthritis. Challenges in the application of this approach are that therapies targeting the osteoclast would need to be used in combination with effective anti-inflammatory agents, and that pathways mediating osteoclast differentiation and function would need to remain at least partially functional to allow for continued skeletal remodeling.

Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. · Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia. · Rheumatology (Oxford). · Pubmed #16490750 links to  free full text

Abstract: OBJECTIVES: Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappaB (RANK) in RA at sites of articular bone erosion. METHODS: Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannus-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion. RESULTS: Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression. CONCLUSIONS: The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.