Bone and Mineral Metabolism

Arthur E. Broadus, M.D., Ph.D. (Endocrinology) The parathyroid hormone-related protein (PTHrP) was discovered by Dr. Broadus’ laboratory in the late 1980’s as the tumor product that mediates the common syndrome of humoral hypercalcemia of malignancy. Work for the past 15 years has focused on the normal biological functions of PTHrP. These include developmental regulatory effects such as the control of endochondral bone formation, mammary epithelial morphogenesis, and tooth eruption. In the adult, PTHrP mediates smooth muscle tone in the vasculature and structures such as the uterus. A recently developed PTHrP-lacZ knock-in “marker” mouse has enabled the identification of PTHrP expression in previously unrecognized sites such as articular cartilage, the periosteum, and the insertion sites of tendons and ligaments into cortical bone. These sites of expression may provide insight into the pathogenesis of disorders such as osteoarthritis.

Thomas Carpenter, M.D. (Pediatric Endocrinology) Dr. Carpenter has had a long interest in metabolic bone diseases in children. In particular, his research incorporates clinical, basic, and translational projects related to disorders of phosphate homeostasis. His program has two major areas of interest: one on phosphate metabolism and another on nutritional rickets. His community study of nutritional rickets and skeletal health in inner city New Haven has recruited over 700 subjects. His research on phosphate metabolism centers on X-linked hypophosphatemic Rickets (XLH). Ongoing projects involve both clinical and animal studies examining the role of PTH in the skeletal abnormalities in XLH and the relative roles of phosphate, PTH and FGF23 in mediating the abnormal growth plate. Finally, his group is also involved in developing new pharmacological antagonists of FGF23 as potential therapeutic agents to treat XLH.

Caren Gundberg, Ph.D. (Orthopedics) Dr. Gundberg’s laboratory is interested in determining the function of non-collagenous matrix proteins in bone with an emphasis on osteocalcin, a vitamin K-dependent protein synthesized only in bone. Recent studies suggest that osteocalcin is involved in the endocrine regulation of energy metabolism. Her lab has initiated studies in mice and humans to test this hypothesis. In mice she is evaluating the direct effect of osteocalcin on the regulation of adiponectin in adipocytes. Since osteocalcin is a vitamin K dependent protein, her group is studying the effect of dietary intake of phylloquinone on the incidence of diabetes.

Mark Horowitz, Ph.D. (Orthopedics) Factors that regulate early B lymphocyte (B cell) development also appear to be essential for normal skeletal development. Dr. Horowitz’s lab has begun an analysis of mice deficient in Ebf1 and Pax5, transcription factors required for B cell fate specification and differentiation. Ebf1 deficient mice are runted, express craniofacial changes, have increased bone formation parameters, and a striking increase in osteoblasts. Remarkably, these mice also exhibit a dramatic expansion of adipocytes in the medullary canal of long bones. Pax5-/- mice are missing 65% of their bone mass due to a 5-fold increase in osteoclast number while their osteoblast number and function are normal. A working hypothesis is that Ebf1 and Pax5 and their upstream regulatory and downstream target genes are critical for the control of alveolar, craniofacial, and long bone development. The long-term goal of our work is to identify the mechanism(s) by which Ebf1 and Pax5 affect bone growth and development and maintain the balance between osteoblastogenesis and adipogenesis.

Karl Insogna, M.D. (Endocrinology) Dr. Insogna maintains active programs in both clinical and bench research. In the clinical arena, Dr. Insogna is interested in the role of dietary protein in skeletal metabolism. He and Dr. Jane Kerstetter have found that increases in dietary protein improve intestinal calcium absorption, rather than increase bone resorption, as had been previously thought. Data from initial studies have led to an NIH-funded, multi-center trial examining the impact of a dietary protein supplement on bone metabolism in postmenopausal women. Another area of active clinical investigation involves understanding the factors that lead to skeletal disease in adult patients with X-linked hypophosphatemic rickets. Finally, Dr. Insogna and Dr. M. Tish Knobf from the School of Nursing are beginning an NIH-funded study to examine the impact of exercise on bone health in postmenopausal breast cancer survivors. In the laboratory, Dr. Insogna’s interest focuses on cellular mechanisms of PTH-induced bone resorption and bone anabolism. Another major research effort in the laboratory is to define the role of the two Colony Stimulating Factor-1 (CSF1) isoforms in bone. Selective deletion of each isoform in vivo is being pursued to better define their separate roles. The laboratory is also interested in the molecular mechanisms by which CSF-1 induces cytoskeletal remodeling and osteoclast motility. Finally, his laboratory is interested in Wnt signaling and its role in lineage allocation in bone.

Richard Lifton, M.D., Ph.D. (Genetics, HHMI) Dr. Lifton's laboratory has used molecular genetic analysis to dissect physiologic processes that regulate cardiovascular and other function in humans, with an emphasis on blood pressure regulation. By coupling the characterization of hundreds of families from around the world with human genetic studies, his group has mapped over 30 human disease genes and has identified functional mutations underlying 22 of these. These have provided new insight into the mechanisms underlying hypertension, stroke, osteoporosis, and renal diseases including disorders of electrolyte and pH homeostasis. Most significantly, by the study of rare families with Mendelian forms of severely high or severely low blood pressure, his laboratory has identified mutations in 16 individual genes that all converge on the same final common pathway, altering net renal salt reabsorption, providing definitive evidence that mutations that increase net salt balance raise blood pressure in humans. Recent studies have also identified human mutations in LRP 5 and 6, mediators of the Wnt signaling cascade, that generate alterations in bone mass and also reproduce aspects of the metabolic syndrome, underscoring the importance of this pathway in both bone and carbohydrate metabolism.

Dan Wu, Ph.D. (Pharmacology) The long-term goal of the Wu laboratory is to understand the molecular basis and function of signal transduction pathways, with the emphasis on those initiated by seven-transmembrane receptors. Currently, his group is focusing on chemoattractant and Wnt-activated signaling. The Wnt family of secretory glycoproteins participates in a wide variety of developmental events including control of cell growth, generation of cell polarity, and specification of cell fate. Wnt pathways have been also closely linked to tumorigenesis and bone formation. The most notable contribution from Dr. Wu’s lab was the discovery of the interaction between Wnt coreceptor LRP-5 and Axin, which provided the first connection from a Wnt receptor to an intracellular signaling component and the characterization of the role of Dkk2 in the regulation of osteogenic differentiation. His lab continues to work on the elucidation of fundamental mechanisms of Wnt signaling and characterization of its role in osteoporosis, metabolic syndrome, diabetes, and tumorigenesis, using computation-based virtual screening and chemical genomic approaches.

John Wysolmerski, M.D. (Endocrinology) Dr. Wysolmerski’s laboratory focuses on the function(s) of parathyroid hormone-related protein (PTHrP) during mammary gland development and the contribution of PTHrP to mineral and bone metabolism during lactation. Ongoing projects are examining the interactions between the PTHrP, BMP and Wnt signaling pathways and how they regulate specific transcription factors such as Lef1, Msx2 and Id-1 in regulating embryonic mammary development. The Wysolmerski laboratory is also currently examining how PTHrP and EGFR signaling interact in mammary stromal cells to regulate cellular proliferation and apoptosis in terminal end-buds in response to estrogen. PTHrP also has important functions as a circulating hormone during lactation and the Wysolmerski lab is currently examining several aspects of calcium and bone metabolism during lactation. The lab is examining the mechanisms by which the skeleton repairs itself after lactation as a paradigm for new anabolic therapies for osteoporosis. Finally, his group is examining the molecular mechanisms by which the calcium-sensing receptor regulates PTHrP secretion and calcium transport in normal mammary epithelial cells and in breast cancer cells.