Research Overview
Endocrine and genetic disorders of mineral metabolism
The major objective of the laboratory is to elucidate genetics and the pathogenesis of metabolic bone diseases and to develop new therapies for treating these diseases. I. Gallium Nitrate: Several models of mature osteoblasts have been used to study the cellular actions of gallium. Transient and stably transfected osteoblasts have been used to study the effects of gallium on specific matrix genes. Various aspects of cell-signaling that can lead to alterations in bone-matrix gene expression have been studied. We hope that such studies will provide the scientific rationale for the development of clinical protocols studying the ability of gallium to prevent and treat osteoporosis. II. Cell and Molecular Regulation of Collagenase Gene Expression: Cell mediated damage to the major matrix components of connective tissues is an early and critical step in the pathogenesis of destructive arthritic diseases. Type I collagen is the major organic component of bone. In order to develop new therapeutic strategies for preserving and protecting connective tissue, a better understanding of the cellular controls on the degradation and synthesis of the key matrix components is required. Our preliminary studies in synoviocytes and fibroblasts showed that PGE1 and activators of adenyl cyclase suppressed collagenase gene expression. PGE1 appears to act via the cyclic adenosine monophosphate/protein kinase A- pathway to ultimately inhibit collagenase gene expression. We were the first to describe this molecular effect and to provide evidence that this effect is probably mediated through novel inhibitory sequences in the proximal portion of the 5'-flanking region of the collagenase gene. III. Clinical Trials in Osteoporosis and Paget's Disease of Bone: We have participated in several multi-center drug trials examining the safety and efficacy of new bisphosphonates as well as PTH-fragments for preventing fractures and preserving bone mass in patients with osteoporosis and vertebral fractures.
