ASGSB 1998 Annual Meeting Abstracts

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LOCAL REGULATION OF ENDOCHONDRAL DEVELOPMENT BY STEROID HORMONES AND GROWTH FACTORS. B.D. Boyan¹ and Z. Schwartz^1,2. ¹University of Texas Health Science Center at San Antonio, Texas and ²Hebrew University, Jerusalem, Israel.

Growth plate development involves the synthesis, maturation, and mineralization of the extracellular matrix by chondrocytes, a process that is under both systemic and local regulation and involves extracellular organelles called matrix vesicles. Studies in our lab have shown that resting zone chondrocytes [RC] produce and maintain a proteoglycan rich matrix under regulation of 24,25-(OH)2D3 [24,25]. 24,25 induces these cells to become responsive to 1,25-(OH)2D3 [1,25], which is the hallmark of growth zone chondrocytes [GC] derived from the prehypertrophic and upper hypertrophic zones of the growth plate. This effect of 24,25 is potentiated by TGF- . GC cells produce matrix vesicles that are enriched in alkaline phosphatase and matrix metalloproteinase activity. Both cell types produce 1,25 and 24,25 locally and secrete these metabolites under growth factor and hormonal control into the extracellular matrix, resulting in differential regulation of the matrix vesicles, thereby permitting regulation of events at sites distant from the cell. One consequence of the action of 24,25 and 1,25 on RC and GC cells is the differential synthesis of latent TGF- binding protein, and therefore, the incorporation of latent TGF- into the matrix. GC matrix vesicles treated directly with 1,25 can activate latent TGF- . TGF- regulates the 1 and 24R hydroxylases involved in production of 1,25 and 24,25. This results in a feed-back loop between the local production, storage and activation of the growth factor. The sex steroids estrogen and testosterone also exert direct effects on the chondrocytes and matrix vesicles via cell maturation-dependent mechanisms. 1,25, 24,25, estrogen, and testosterone exert their effects via rapid membrane-mediated mechanisms involving membrane fluidity, specific membrane receptors, calcium ion fluxes, changes in lipid metabolism, and PKC, as well as by conventional steroid hormone-dependent pathways. (Supported by NIH: DE-05637 and DE-08603.)

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