Endocrinology and Metabolism

Clinical and basic biomedical research in the Division is Endocrinology and Metabolism is concentrated in the fields of bone and mineral metabolism and in endocrine neoplasia. Specific areas of investigation include osteoporosis; tumors of the parathyroid and thyroid glands; endocrine hypertension; Paget’s disease of bone; endocrine/bone issues in patients being treated for breast and other cancers; interactions of the immune system with bone biology; role of growth factors, bone matrix proteins, prostaglandins, and other molecules in regulation of bone cell function; and clinical diabetes care. Specific information about each faculty member’s research can be found below:

Andrew Arnold, M.D.  The most longstanding interest of Dr. Arnold’s laboratory has been in the molecular genetic underpinnings of tumors of the endocrine glands. It was in the context of a search for a parathyroid tumor oncogene lying adjacent to a clonal chromosomal breakpoint that the lab discovered cyclin D1 (PRAD1). Cyclin D1 has proven to play a key role in cell cycle regulation, and has emerged as a major human oncogene, important in multiple types of tumors including breast cancer and B-cell lymphoma. The lab is currently pursuing a number of approaches, including the use of transgenic mouse models, to learn more about the precise mechanisms by which cyclin D1 exerts its oncogenic effects. In addition to the cyclin D1 work, the lab continues a major initiative seeking additional genes that contribute to endocrine neoplasia. In this context, teh lab identified the HRPT2 gene as a major factor in the development of malignant parathyroid tumors, a finding that carries important clinical implications.

Marja Hurley, M.D.  Dr. Hurley’s laboratory examines molecular mechanisms by which members of the fibroblast growth factor (FGFs) and fibroblast growth factor receptor (FGFR) families, regulate bone development, remodeling and disorders of bone. FGF-2 knockout and FGF-2 transgenic mice are utilized in loss and gain of function experiments to elucidate the role of FGF-2 in disorders of bone. The lab was the first to demonstrate an important role for FGF-2 in the maintenance of bone mass. Subsequent mechanistic studies showed that loss of endogenous FGF-2 resulted in lineage change resulting in reduced osteoblast and osteoclast progenitors and increased marrow adipocytes and impaired Wnt signaling. This work was extended to demonstrate an important role for endogenous FGF-2 as an intermediary growth factor in the osteoblast responses to PTH), BMP2), TGFβ) and prostaglandins in bone. Dr. Hurley’s group has made seminal contributions to our understanding of FGF-2 mechanism of action in bone in an effort to elucidate contributing factors to osteoporosis and bone repair especially with age. Part of this work was to understand the role of FGF-2 signaling via Wnt in the anabolic response to PTH and BMP-2. Specifically, the bone in vivo anabolic response to both PTH and BMP2 is markedly impaired in FGF-2 KO mice. Of potential translational relevance, in collaborative studies, in humans treated with human parathyroid hormone for glucocorticoid induced osteoporosis, Dr. Hurley’s group reported that PTH increased serum levels of FGF-2 in these patients and this increase was correlated with increased serum markers of bone formation. Dr. Hurley’s recent work has focused on the novel role of the nuclear localized high molecular weight isoforms (HMW) of FGF-2 whose biological functions in bone was previously unknown. The lab was the first to demonstrate the presence of these isoforms in osteoblasts and osteocytes and utilized transgenic over expression and knockout of FGF-2 isoform(s) mice to demonstrate their importance in phosphate homeostasis and regulation of FGF23. The clinical translational relevance of these isoforms to human phosphate wasting disorders is being investigated since they were also increased in osteoblasts and osteocytes of the Hyp mouse model of X-linked hypophosphatemic rickets.

Barbara Kream, Ph.D.  Mechanisms by which hormones and growth factors such as insulin-like growth factor and glucocorticoids regulate bone remodeling in postnatal life.

Joseph Lorenzo, M.D.  The focus of Dr. Lorenzo’s lab is the influence of hormones and cytokines on both bone resorption, which is mediated by osteoclasts, and bone formation, which is mediated by osteoblasts. The lab studies the nature and regulation of osteoclast precursor cells in health and disease and the influence of the immune system on bone remodeling. The lab is actively involved in research that is designed to identify the surface markers of cells that differentiate into osteoclasts in vitro and in vivo. The goal of these studies is to characterize the cells that form osteoclasts and determine if there are differences between them in normal and pathologic conditions. Dr. Lorenzo’s lab also studies the role that the transcription factor Runx1 has on osteoclasts formation and function. It is hoped that this research will lead to the development of targeted therapies that selectively inhibit pathologic osteoclast formation without affecting normal bone turnover.

Clinical Research Interests: Small projects that study the role of hormones in the regulation of serum sclerostin and osteoclast precursor cells.

Pooja Luthra, M.D.  Dr. Luthra is interested in diabetes and thyroid disorders with special focus on intensive diabetes management with insulin pumps and continuous glucose monitoring. She is also an expert in endocrine issues during pregnancy including gestational diabetes and thyroid disorders. Her other areas of expertise include endocrine neoplasia and management of thyroid nodules and thyroid cancer.

Carl Malchoff, M.D.,  Ph.D.  Dr. Malchoff has a general interest in the molecular pathogenesis of tumors of the thyroid, adrenal, and pituitary gland. Specific research interests include familial papillary thyroid carcinoma, autoimmunity in thyroid cancer, and primary aldosteronism. He has published over 45 peer-reviewed manuscripts and over 35 invited reviews.

Faryal Mirza, M.D.  Dr. Mirza has special interests in bone health and osteoporosis, metabolic bone disease, gender biology, and physiological changes with menopause. Other areas of expertise include general endocrine disorders including diabetes and thyroid disorders. She is involved in translational research on the role of sclerostin in bone health. She also does clinical research in bone and blood pressure issues in postmenopausal women with breast cancer. She actively teaches future physicians and is the director of the ambulatory medicine rotation for third year medical students at the UConn School of Medicine.

Carol Pilbeam, M.D., Ph.D.  Regulation and function of cyclooxygenase-2 (COX-2) in bone. COX-2 is responsible for most prostaglandin regulation in bone. Ongoing research projects include examination of transcriptional regulation of COX-2 in osteoblastic cells and examination of the effects of COX-2 gene disruption on bone resorption and formation. Dr. Pilbeam’s lab is particularly interested in the inhibition by COX-2 of the anabolic effects of PTH on bone, an effect that appears to be mediated by cells of the osteoclast lineage. The role of COX-2 in the osteoblastic response to mechanical loading. COX-2 may mediate effects of mechanical loading on bone. The lab is studying fluid shear stress induction of COX-2 expression involving signaling pathways and transactivating factors.

Pamela Taxel, M.D. – Her clinical area of focus is in the treatment of patients with osteoporosis, with a special interest in the treatment of men and women receiving cancer therapies that impact bone health. She collaborates with School of Dental Medicine colleagues in several research projects including a study assessing the impact of bone health on implant success or failure, as well as another project on the identification of risk factors for osteonecrosis of the jaws in patients receiving bone-modifying therapies for advanced cancers.

Beatriz Tendler, M.D. – Dr. Tendler pursues research in primary hyperparathyroidism and thyroid carcinoma. Her current research focuses on familial thyroid cancer.

Liping Xiao, M.D., Ph.D., MSCTR  Dr. Xiao pursues basic research to elucidate the molecular mechanism(s) in hereditary hypophosphatemic rickets. Another research interest involves utilization of mouse models and induced pluripotent stem cells (iPSCs) to study psychiatric disorders/antipsychotics and their bone related complications. Her current research focuses on fibroblast growth factor 2 isoforms and fibroblast growth factor 23.