Chondrocyte calcium-sensing receptor expression is up-regulated in early guinea pig knee osteoarthritis and modulates PTHrP, MMP-13, and TIMP-3 expression.
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.
Burton
D W
DW
San Diego Veterans Administration Healthcare System, San Diego, CA 92161, USA.
Foster
M
M
Johnson
K A
KA
Hiramoto
M
M
Deftos
L J
LJ
Terkeltaub
R
R
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D017364:Collagenases / Q000032:analysis*; D006168:Guinea Pigs; D006614:Hindlimb; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D053509:Matrix Metalloproteinase 13; D010003:Osteoarthritis / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000032:analysis*; D044169:Receptors, Calcium-Sensing / Q000032:analysis*; D018016:Receptors, Parathyroid Hormone / Q000032:analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis*; D015854:Up-Regulation / Q000502:physiology
D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing; D018016:Receptors, Parathyroid Hormone; D019717:Tissue Inhibitor of Metalloproteinase-3; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13