UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

My work explores how ions and autocrine/paracrine factors impact cartilage development. One project investigates the role of Ca 2+ , insulin like growth factor (IGF)-1 and its receptor in chondrocyte differentiation. We use primary cultures of bovine and murine growth plate chondrocytes (GPCs) as well as genetically manipulated mouse models to address mechanisms responsible for the ionic and hormonal control of chondrocyte differentiation. We found that changes inthe extracellular [Ca 2+ ] ([Ca 2+ ] e) strongly influence the differentiation of GPCs in culture. These cells also express “parathyroid-like” CaRs which are candidates for coupling the changes in [Ca 2+ ] e to subsequent cell responses. Studies have been performed to determine the impact of this receptor on chondrocyte differentiation in vitro. Mice with cartilage-specific knockout of the CaR gene are being generated to assess its role in vivo. We have generated cartilage-specific IGF-1 and IGF-1R knockout mice by Cre/Lox recombination. Deleting the IGF-1R in cartilage causes growth retardation of the mice, and these mice die immediately after birth. Bone histomorphometry and µ-CT imaging techniques are used to further analyze skeletal phenotypes of the mice. Gene expression profiles in IGF-1R-knockout chondrocytes will be assessed by a custom mouse microarray to identify signaling molecules associated with IGF-1/IGF-1R signaling in these cells. Another project explores the potential autocrine/paracrine action of g -aminobutyric acid (GABA) type B receptors (Gabbrs) in growth plate development. Gabbrs are strongly expressed in the growth plate chondrocytes as well as glutamic acid decarboxylase 65/67 (GAD65/67), which converts glutamate to GABA, suggesting that GABA signaling may play a role in the differentiation of chondrocytes. We are generating cartilage-specific knockout of the Gabbr1 to address its role in vivo.

Selected References

W Chang, and D Shoback. 2004 Extracellular Ca 2+ -sensing receptors – an overview. Cell Calcium 35: 183-196.

L Rodriguez, Z Cheng, T-H Chen, C Tu, W Chang. 2005 Extracellular calcium and parathyroid hormone-related peptide signaling modulate the pace of growth plate chondrocyte differentiation. Endocrinology 146:4597-608

L Rodriguez, C Tu, , Z Cheng, T-H Chen, D. Bikle, D Shoback, W Chang. Expression and functional assessment of an alternatively spliced extracellular Ca2+-sensing receptor in growth plate chondrocytes . Endocrinology 146:5294-303

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