Chondrocyte calcium-sensing receptor expression is up-regulated in early guinea pig knee osteoarthritis and modulates PTHrP, MMP-13, and TIMP-3 expression

Osteoarthritis Cartilage. 2005 May;13(5):395-404. doi: 10.1016/j.joca.2005.01.002.

Abstract

Objective: Growth plate chondrocytes up-regulate calcium-sensing receptor (CaR) expression as they mature to hypertrophy. In cells other than chondrocytes, extracellular calcium-sensing via the CaR functions partly to promote expression of parathyroid hormone-related protein (PTHrP), a critical regulator of endochondral development. Moreover, PTHrP is up-regulated in human osteoarthritis (OA) and surgically induced rabbit OA cartilages and may promote both chondrocyte proliferation and osteophyte formation therein. Hence, we examined chondrocyte CaR-mediated calcium-sensing in OA pathogenesis.

Methods: We studied spontaneous knee OA in male Hartley guinea pigs. We also evaluated cultured bovine knee chondrocytes and immortalized human articular chondrocytes (CH-8 cells), employing the CaR calcimimetic agonist NPS R-467 or altering physiologic extracellular calcium (1.8 mM).

Results: Immunohistochemistry revealed that CaR expression became up-regulated in the superficial zone at 4 months of age in the guinea pig medial tibial plateau cartilage as early OA developed. CaR expression later became up-regulated in the middle zone. PTHrP content, measured by immunoassay, was significantly increased in the medial tibial plateau cartilage as OA developed and progressed. In cultured chondrocytic cells, CaR-mediated extracellular calcium-sensing, stimulated by the calcimimetic NPS R-467, induced PTHrP and matrix metalloproteinase (MMP)-13 expression and suppressed expression of tissue inhibitor of metalloproteinase (TIMP)-3 dose-dependently, effects shared by elevated extracellular calcium (3 mM). Extracellular calcium-sensing appeared essential for PTHrP and interleukin (IL)-1 to induce MMP-13 and for PTHrP 1-34 to suppress TIMP-3 expression.

Conclusions: Chondrocyte CaR expression becomes up-regulated early in the course of spontaneous guinea pig knee OA. Chondrocyte CaR-mediated extracellular calcium-sensing promotes PTHrP expression, modulates the effects of PTHrP and IL-1, and promotes MMP-13 expression and TIMP-3 depletion. Our results implicate up-regulated extracellular calcium-sensing via the CaR as a novel mediator of OA progression.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cartilage, Articular / metabolism
  • Cattle
  • Cells, Cultured
  • Chondrocytes / metabolism*
  • Collagenases / analysis*
  • Guinea Pigs
  • Hindlimb
  • Immunohistochemistry / methods
  • Male
  • Matrix Metalloproteinase 13
  • Osteoarthritis / metabolism*
  • Parathyroid Hormone-Related Protein / analysis*
  • Receptors, Calcium-Sensing / analysis*
  • Receptors, Parathyroid Hormone / analysis
  • Tissue Inhibitor of Metalloproteinase-3 / analysis*
  • Up-Regulation / physiology

Substances

  • Parathyroid Hormone-Related Protein
  • Receptors, Calcium-Sensing
  • Receptors, Parathyroid Hormone
  • Tissue Inhibitor of Metalloproteinase-3
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13