Chondrocalcinosis occurs in a variety of metabolic and rheumatologic conditions including pseudogout, primary hyperparathyroidism (HPTH), and familial benign hypocalciuric hypercalcemia (FBHH). Chondrocalcinosis results from the deposition of calcium pyrophosphate dihydrate and basic calcium phosphate in articular cartilage. The mechanisms underlying crystal formation and the joint destruction that results from the associated inflammation are poorly understood. Studies indicate that overproduction of Pi and PPi, and excess Ca2+ may play a pivotal role in initiating and/or promoting pathologic crystallization . Our recent studies indicated that changes in the extracellular Ca2+ concentration ([Ca2+]o) modulate important functions in chondrocytes and chondrogenic RCJ3.1 C5.18 cells. These functions include the expression of the enzyme alkaline phosphatase (ALP), which cleaves P; from acidic phospholipids and PPi. Changes in [Ca2+]o regulate important functions in parathyroid and kidney cells by activating extracellular Ca2+-sensing receptors (Cans) that are coupled to signal transduction. CaRs are also strongly expressed in articular chondrocytes. Mutations in the CaR gene cause FBHH, in which there is an increased incidence of chondrocalcinosis. Another hypercalcemic state, primary HPTH, is also associated with increased prevalence of chondrocalcinosis. It appears that chronic increases in systemic Ca2+ or reduced Ca2+-sensing ability are associated with the deposition of pathological crystals in articular cartilage. We hypothesize that articular chondrocytes express CaRs that detect changes in [Ca2+]o and regulate the expression and activity of enzymes important in normal mineralization in cartilage and also in the pathological deposition of Ca2+- containing crystals. To address our hypothesis, we will: (1) determine whether there is a Ca2+-sensing mechanism in articular chondrocytes that is functionally coupled to signaling pathways; (2) examine whether changes in [Ca2+]o alter the expression of genes important in setting the concentrations of Pi and PPi in cartilage; and (3) determine whether the effects of extracellular Ca2+, cations, or calcimimetics are mediated via CaRs in articular chondrocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Comprehensive Center (P60)
Project #
5P60AR020684-24
Application #
6422912
Study Section
Special Emphasis Panel (ZAR1)
Project Start
1977-09-15
Project End
2002-12-31
Budget Start
Budget End
Support Year
24
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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