Endocrine Unit Research Lab

About the Lab

In recent years, areas of particular interest have included:

• Studies of parathyroid hormone (PTH) structure, biosynthesis and action
• Analysis of the pathogenesis of parathyroid neoplasms
• The use of parathyroid hormone as a therapeutic agent for human osteoporosis
• The study of the regulation of gene expression by vitamin D and the role of the vitamin D receptor as revealed by study of "knockout" mice
• The study of the regulation of bone development and growth, including the effects of PTHrP and the roles of micro RNAs
• The identification of early cells of the osteoblast lineage in vivo and analysis of factors that change the fates of these progenitor cells

Long-acting analogs of PTH are being developed as possible therapies for primary hypoparathyroidism in people. Studies of FGF23, the recently described regulator of phosphate homeostasis, have involved a series of clinical and basic investigative studies. Clinical studies have also focused on the roles of androgens and estrogens on bone and other targets in males, the various roles of vitamin D and an analysis of the effectiveness of current therapies for primary hypoparathyroidism. New clinical work examines the microarchitecture of human bone noninvasively. This work is funded primarily by the National Institutes of Health (NIH), by NIH program projects and by pharmaceutical company support.

Group Members

Research Projects

Recent research accomplishments in the Endocrine Unit include:

• The cloning of cDNA and genomic DNA encoding the PTH/parathyroid hormone-related protein (PTHrP) receptor. Studies of the cloned receptor show that it mediates the actions of both ligands and stimulates multiple intracellular pathways
• Demonstration that the formerly puzzling Jansen-type metaphyseal osteochondrodystrophy is a disease of the PTH/PTHrP receptor. Analysis of the mutant genes explains the disease and sheds fresh light on receptor function
• Detailed analysis of the modes of activation of the PTH/PTHrP receptor by PTH and PTHrP analogs. This analysis has led to novel hypotheses about receptor activation and the design of the long-acting PTH analogs that are being developed for therapy of primary hypoparathyroidism in humans
• The identification and cloning of the PRAD 1 gene, a novel cyclin gene overexpressed in a subset of parathyroid and other tumors. Further analysis has shown that many patients with apparent parathyroid hyperplasia have clonal expansions complicating the hyperplastic process and has identified the locations of abnormal genes in the majority of parathyroid adenomas
• Studies of the role of GCMB as a master regulator of parathyroid development and studies of the effectiveness of current therapies for primary hypoparathyroidism
• The demonstration in men and women that parathyroid hormone can dramatically increase bone mass and prevent fractures with further studies showing the effects of combining PTH and bisphosphonate therapy
• The delineation of normal functions of PTHrP and the PTH/PTHrP receptor in bone development through the construction and analysis of mice missing the genes encoding either the PTHrP or the PTH/PTHrP receptor. Animals missing either gene die at birth or earlier with a chondrodysplasia and defects in fetal calcium metabolism
• A detailed analysis of specific residues of the PTH/PTHrP receptor involved in binding ligand in transmitting the changes caused by ligand binding across the plasma membrane and in activating specific G proteins. These mutants allow the correlation of specific second-messenger pathways with specific biologic actions of PTH
• Analysis of the mechanisms used by PTH to regulate phosphate handling by the renal proximal tubule
• Use of drosophila genetics to explore the mechanisms of phosphate sensing in normal physiology and in renal disease
• Studies of the role of phosphate in mediating the normal function of the growth plate and avoidance of rickets
• Analysis of the molecular pathogenesis of pseudohypoparathyroidism, type 1b (an imprinting disorder) and the normal roles of XL, an extra-large variant of Gsa
• The characterization of vitamin D receptor (VDR) "knockout" mice that have abnormalities of bone and calcium metabolism that can be reversed with a "rescue" diet and also have a unique form of alopecia that cannot be reversed by normalization of calcium metabolism and reveal interactions of VDR and wnt signaling
• The identification of mutations in people with a broad array of inherited diseases of bone and mineral metabolism: imprinting mutations in pseudohypoparathyroidism 1b, mutations in NaPi2c in hereditary hypophosphatemia with hypercalciuria, mutations in collagen I(a1) in Caffey disease, and mutations in dentin matrix protein-1 in autosomal recessive hypophosphatemic rickets
• Studies in humans of the anabolic actions of PTH (1-34) and ways to improve anabolic therapies by combining PTH (1-34) with denosumab
• Studies of the distinct roles of androgen and estrogen in influencing bone health
• Studies of male hypogonadism with the goal of defining the levels of androgen replacement necessary to reverse abnormalities in various target tissues along with defining the roles of conversion of androgens to estrogens in mediating these functions
• Studies of the roles of FGF23 in normal physiology and disease in humans and experimental animals
• Studies of the effects of bariatric surgery on bone health
• Studies of the actions of PTH on osteocytes and the role of osteocytes in mediating effects of unloading on bone
• Studies of the determinants of bone strength in humans and experimental animals
• Demonstration that histone deacetylases 4 and 5 mediate the actions of the PTH/PTHrP receptor in growth plate cartilage to suppress differentiation and in osteocytes to decrease expression of the sclerostin gene
• Identification of growth-associated stem cells in bone that generate osteoblasts, adipocytes and chondrocytes in vivo

Our Investigators

Our investigators range from bench scientists to translational researchers.