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  • Oral presentation
  • Open Access

Cell biology of synovial inflammation and secondary osteoporosis in rheumatoid arthritis

  • 1,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 1
Arthritis Res Ther20035 (Suppl 3) :45

https://doi.org/10.1186/ar846

  • Published:

Keywords

  • Rheumatoid Arthritis
  • Bone Resorption
  • Secondary Osteoporosis
  • Rheumatoid Synovium
  • Synovial Proliferation

Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by lymphocyte accumulation and synovial proliferation, which are induced by inflammatory cytokines and adhesion molecules. Although periarticular as well as systemic osteoporosis and subsequent joint destruction are major complications of RA, the precise mechanisms remain unclear. Osteoblasts not only play a central role in bone formation by synthesizing bone matrix proteins, but they regulate osteoclast maturation by cognate interaction, resulting in bone resorption. RANKL expressed on osteoblasts provides essential signals to osteoclast progenitors for their maturation. We have proposed that the LFA-1/ICAM-1-mediated adhesive pathway of osteoblasts is required for juxtacrine stimulation of osteoclast maturation by membrane-bound RANKL on osteoblasts. Moreover, proinflammatory cytokines such as IL-1 produced abundantly in rheumatoid synovium induce both RANKL and ICAM-1 on osteoblasts, leading to an efficient juxtacrine stimulation for the osteoclastogenesis. However, ICAM-1-positive osteoblasts, induced by IL-1, arrest at the G0/G1 phase of the cell cycle, which is involved by upregulation of p21 and reduced activities of cdk6. IL-1-induced ICAM-1-positive osteoblasts can bias bone turnover to bone resorption, committing their growth arrest, in the context of the balance between survival and apoptosis of the cells. Such a regulation of the cell cycle is regulated by H-Ras, a small G-protein. H-Ras signals followed by Raf-1/MAPK induce cell-cycle arrest of osteoblasts via Fas upregulation and bcl-2 downregulation, whereas H-Ras followed by PI3K induces their proliferation. Taken together, during bone remodelling processes, proinflammatory cytokines cause an imbalance in bone metabolism by favouring bone resorption via the expression of RANKL and ICAM-1, as well as apoptosis of osteoblasts, which are differentially regulated by intracellular signals via H-Ras. Such osteoclast maturation mediated by the adhesion with osteoblasts is coordinated with immune signaling, and thereby is relevant to pathological events such as secondary osteoporosis observed in RA.

Authors’ Affiliations

(1)
First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan

Copyright

© The Author(s) 2003

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