Bone resorption by osteoclasts depends on an incompletely defined sequence of cellular events beginning with attachment bo bone matrix. Matrix attachment is mediated by the integrin avbeta3 and thus, regulation of the integrin complex on the cell surface represents a logical approach to controlling the resorptive process. We find that 1,25-dihydroxyvitamin D3 (1alpha, 25(OH), 2D3), which prompts osteoclast differentiation in vivo and in vitro, transcriptionally activate expression of integrin beta3 gene promoter region. The result in an enhanced expression of alphavbeta3 on the surface of avian osteoclast precursors. CRT is a multifunctional protein that acts as a major Ca2+ binding protein in the lumen of the endoplasmic reticulum and in the nucleus. It binds to the first zinc finger of steroid hormone receptors such as VDR, and prevents them from binding to their sterid hormone response elements. As a result, CRT modulates sterid hormone receptor-mediated gene transactivation. Furthermore, we have shown direct interaction between the VDR and calreticulin. Our central hypothesis is that the interaction of calreticulin and VDR modulates VDR genomic activity. The studies in his application are designed to establish the action of calreticulin on VDR-mediated gene transactivation and to elucidate the calreticulin function through the interaction of VDR and calreticulin.
Our specific aims are to: 1 Analyze the effects of CRT on 1alpha,25(OH)2D3-mediated again beta3 gene expression in osteoclast precursors. 2) Analyze the effects of CRT on osteoclast attachment to bone matrix and bone resorption. 3) Determine the role of CRT and VDR interaction in the translation of VDR into the nucleus.
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