Bone and Mineral Metabolism

The program in bone and mineral metabolism includes Drs. Insogna, Carpenter, Sharkey, Bergwitz and Wysolmerski. Research by these investigators focuses on the biology of PTHrP in cartilage and mammary gland; bone cell biology; skeletal metabolism and osteoporosis; calcium metabolism during lactation and the transport of calcium into milk; the role of dietary protein in calcium and bone metabolism; and the pathogenesis and treatment of disorders of phosphate metabolism, especially X-linked hypophosphatemic rickets.

Faculty

Endocrinology

Clemens Bergwitz, MD

Dr. Bergwitz is board certified in Internal Medicine and Endocrinology. He serves as attending on the endocrine inpatient consult service at YNHH and sees outpatients with a focus on disorders of mineral and metabolism and endocrine oncology as a member of the Yale Medical Group at the Multispecialty Clinic of Smilow Cancer Center. He is a certified clinical densitometrist at the Yale Bone Center. 

His research interest is in translational and basic research on inborn errors of phosphate metabolism and the endocrine regulation of phosphate homeostasis, with emphasis on the metabolic and homeostatic effects of phosphate.

John Wysolmerski, M.D.

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.

Karl Insogna, M.D.

Dr. Insogna maintains active programs in both clinical and translational research. In the clinical arena, Dr. Insogna, in collaboration with Dr. Thomas Carpenter in Pediatrics, has an active investigative program in X-linked hypophosphatemia, the most common inherited hypophosphatemic disorder. Yale is the principal site for a large multi-center trial testing the efficacy of a blocking antibody to FGF23 in the treatment of patients with XLH, as well as patients with tumor-induced osteomalacia. In addition, Dr. Insogna has an investigator-initiated trial exploring the impact of this therapy on trabecular microarchitecture as assessed by Trabecular Bone Score (TBS), and cortical bone quality as assessed by reference point indentation using an Osteoprobe® instrument. He is also pursuing studies exploring the genetic bases for syndromes of low bone mass associated with hypercalciuria and high rates of skeletal remodeling.

In the laboratory, Dr. Insogna’s interests include cellular mechanisms of PTH-induced bone resorption and bone anabolism. A particular focus of this work is on the role of Colony Stimulating Factor 1 (CSF-1) in mediating both the pro-resorptive and anabolic effects of PTH. CSF-1 is one of two principal cytokines required for osteoclastogenesis. Dr. Insogna’s lab has explored the role of the two major CSF isoforms (soluble and membrane-bound) in mediating osteoclastogenesis. He has also studied the downstream signaling pathways activated by CSF-1 binding to its cognate receptor, c-fms, in mature osteoclasts. Most recently, his attention has turned to a possible role for CSF-1 in mediating PTH anabolism via a paracrine circuit that involves osteoclast-generated sphingosine-1 phosphate. The Insogna lab is also interested in osteocyte-mediated mechanotransduction and cellular remodeling using both in vitro and in vivo tools.

Pediatric Endocrinology

Thomas Carpenter, M.D.

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 and vitamin D metabolism. His research on phosphate metabolism centers on X-linked Hypophosphatemic Rickets (XLH) and other clinical disorders of phosphate metabolism. His vitamin D work relates to determinants of vitamin D status in children, with investigations centering on a large cohort of New Haven children. 

 
Ongoing studies include the development of new pharmacological antagonists of FGF23 as potential therapeutic agents to treat XLH and related disorders, as well as investigations of late consequences of the disease, such as myopathy and enthesopathy.