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.

Endocrinology

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.

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.

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

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.

Orthopedics

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.

Dr. Sharkey is a pediatric orthopaedic surgeon who specializes in the surgical treatment of bone deformity and limb length differences, as well as foot deformities. She provides surgical assistance to Drs. Insogna and Carpenter in their clinical research on hypophosphatemic bone diseases. Twice a month, she and Dr. Carpenter host a multidisciplinary clinic for children and young adults with metabolic bone conditions, including X-linked hypophosphatemia. 

Her research interests include the influence of gender on thought leadership and innovation in orthopaedic surgery, abusive fractures in young children, metabolic bone disease, and bone deformity.

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.

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.

Faculty

Clemens W.H. Bergwitz, MD

Assistant Professor of Medicine (Endocrinology)

Thomas Oliver Carpenter, MD

Professor of Pediatrics (Endocrinology) and of Orthopaedics and Rehabilitation and Clinical Professor of Nursing

Mark Charles Horowitz, PhD

Professor of Orthopaedics and Rehabilitation

Karl L. Insogna, MD

Ensign Professor of Medicine (Endocrinology)

Melinda Sharkey, MD

Associate Professor of Orthopaedics and Rehabilitation

Dianqing (Dan) Wu, PhD

Professor of Pharmacology

John Joseph Wysolmerski, MD

Professor of Medicine (Endocrinology)