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Volume 1 Supplement 1

Fourth International Synovitis Workshop

Overview: Destruction of the Extracellular Matrix in Rheumatoid Arthritis

Arthritis Research & Therapy volume 1, Article number: S14 (1999) Cite this article

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A major cause of morbidity in rheumatoid arthritis (RA) is the destruction of the extracellular matrix (ECM) of cartilage, bone, and soft tissues of the joint. Proteolytic enzymes, such as the matrix metalloproteinases (MMPs) and the recently characterized and cloned aggrecanases with disintegrin domains, have a role in these destructive processes that result in loss of fibrillar (collagens) and nonfibrillar components of the ECM. MMPs, eg collagenases, cannot degrade the ECM of mineralized bone, but mechanisms require action of specialized cells (osteoclasts) generated from hemopoietic precursors in marrow and in the inflammatory cell mass. Ligands, which increase bone resorption, initiate osteoclast generation by acting on mesenchymal cells (fibroblasts, stromal cells, and osteoblasts) to induce cell-bound osteoclast differentiation factor (ODF). ODF in turn binds to a receptor (RANK) on osteoclast precursors and, with M-CSF, generates active osteoclasts. Another factor, osteoprotegerin (OPG), binds to ODF (also known as OPGL [ligand]) and inhibits osteoclastogenesis. A potent inducer of ODF is parathyroid hormone-related peptide (PTHrP); receptors for PTH/PTHrP are found on RA synovial fibroblasts, in culture, and by in situ hybridization, and PTH is produced by RA synovium through the action of inflammatory cytokines. There is evidence derived from studies in animal models that the action of collagenase produced by mesenchymal cells is required for PTH/PTHrP-induced osteoclast generation. Delineation of the precise function of the ligands and proteinases described would help in designing therapy to prevent or retard the focal bone erosions and more diffuse bone loss of RA.

References

  1. 1.

    Funk JL, Cordaro LA, Wei H, Benjamin JB, Yocum DE: Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis. J Clin Invest. 1998, 101: 1362-1371.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  2. 2.

    Kohno H, et al: Synovial fluids from patients with osteoarthritis and rheumatoid arthritis contain high levels of parathyroid hormone-related peptide. J Bone Miner Res. 1997, 12: 847-854.

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Kotake S, et al: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator or osteoclastogenesis. J Clin Invest. 1999, 103: 1345-1352.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  4. 4.

    Yoshida T, et al: Production of parathyroid hormone-related peptide by synovial fibroblasts in human osteoarthritis. FEBS Lett. 1998, 433: 331-334. 10.1016/S0014-5793(98)00940-5.

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Krane SM, Zhao W: Collagenase in embryonic development and postnatal remodeling of connective tissues. In Collagenases. Edited by Hoeffler W. Austin: RG Landes Co. 1999, 171-187.

    Google Scholar 

  6. 6.

    Shima YH, et al: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998, 95: 3597-3602. 10.1073/pnas.95.7.3597.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Hsu H, et al: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA. 1999, 96: 3540-3545. 10.1073/pnas.96.7.3540.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  8. 8.

    Suda T, et al: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999, 20: 345-357. 10.1210/er.20.3.345.

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Nagase H, Woessner JF: Matrix metalloproteinases. J Biol Chem. 1999, 274: 21491-21494. 10.1074/jbc.274.31.21491.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Zhao W, Byrne MH, Boyce BF, Krane SM: Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice. J Clin Invest. 1999, 103: 517-524.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  11. 11.

    Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR: Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1999, 152: 943-951.

    Google Scholar 

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Affiliations

  1. Harvard Medical School, Boston, Massachusetts, USA

    Stephen Krane

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  1. Stephen Krane
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Krane, S. Overview: Destruction of the Extracellular Matrix in Rheumatoid Arthritis. Arthritis Res Ther 1, S14 (1999). https://doi.org/10.1186/ar28

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Keywords

  • Rheumatoid Arthritis
  • Collagenase
  • Mesenchymal Cell
  • Bone Erosion
  • Synovial Fibroblast

Arthritis Research & Therapy

ISSN: 1478-6362

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