Endocrinology and Metabolism

Clinical and basic biomedical research in the Division 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 can be found about each faculty member’s research 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, the lab identified the HRPT2 (CDC73) gene as a major factor in the development of malignant parathyroid tumors, a finding that carries important clinical implications. Next-generation sequencing approaches from an international consortium led by Dr. Arnold have further illuminated the genetic landscape of parathyroid carcinoma and again carry key implications for new targeted therapy.

Ernesto Canalis, M.D. – The Canalis laboratory is known for the discovery of skeletal growth factors and has pursued important investigations on the role of growth factors and their antagonists in skeletal function. Dr. Canalis’ group has made seminal contributions to our understanding of the mechanisms of glucocorticoid action in bone in an effort to explain the pathogenesis of glucocorticoid induced osteoporosis and correct the disease. The laboratory’s recent work has centered on factors determining osteoblast cell fate and function. These investigations include studies on the role of Notch signaling and Nuclear factor of activated T cells (NFAT) in osteoblastic cell differentiation. Cellular and genetically engineered mouse models are used for the research conducted by the group. The laboratory is particularly interested in translational research and has created genetically engineered mouse models of Hajdu Cheney Syndrome, a devastating disease characterized by bone loss and fractures. The studies have allowed the team to determine mechanisms of the bone loss and are exploring ways to prevent the skeletal disease. The laboratory has been funded continuously by the National Institutes of Health (NIH) since the 1980’s, and in 1990 received a MERIT Award from the National Institute of Musculoskeletal and Skin Disorders (NIAMS). Currently, the laboratory is funded by NIAMS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Office of Research on Women’s Health.

Anne Delany, Ph.D. – Dr. Delany’s research is focused on understanding the molecular mechanisms regulating bone remodeling, with a particular focus on microRNA-mediated gene regulation. One current project involves the study of the miR-29 family and is role in osteoclastogenesis, utilizing both in vivo and in vitro models. Other projects are focused on miRNA regulation of osteoblast differentiation and function, and the impact of miRNAs on circadian rhythm in bone tissue.

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. Fgf2 global and conditional knockout and Fgf2 isoform transgenic mice are utilized in loss and gain of function experiments to elucidate the role of FGF2 in osteoarthritis, as well as disorders of bone including osteoporosis, and rickets, osteomalacia due to phosphate wasting. Dr. Hurley’s research also involves delineating the epigenetic mechanism by which the nuclear localized high molecular weight isoforms of FGF2 mediate growth-plate abnormalities and osteoarthropathy. 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 my laboratory is the influence of hormones and cytokines on both bone resorption, which is mediated by osteoclasts, and bone formation, which is mediated by osteoblasts. We study the nature and regulation of osteoclast precursor cells in health and disease and the influence of the immune system on bone remodeling. The laboratory 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 different between them in normal and pathologic conditions. We also study 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 3rd year medical students at the UConn School of Medicine.

Carol Pilbeam, M.D., Ph.D. – Dr. Pilbeam’s lab is interested in how prostaglandins (PGs) produced by cyclooxygenase 2 (COX2) regulate bone responses to parathyroid hormone (PTH) and how PGs contribute to the chronic inflammation of aging that leads to bone loss and fragility fractures. Her lab discovered that COX2/PGE2 inhibits the anabolic effects of PTH on bone, and that this inhibition occurs via serum amyloid A3 (SAA3). SAA3 is produced by the osteoclastic lineage cells, in response to PTH-stimulated RANKL and PGE2. SAA3 then acts on the osteoblastic lineage cells to block PTH-stimulated cAMP production and, as a result, osteoblastic differentiation. Continuously elevated levels of SAA3 explain why continuous PTH is catabolic rather than anabolic like intermittent PTH. The lab has generated a global SAA3 knockout mouse, which is being studied, along with the COX2 knockout mouse, for aging-related changes. We have shown SAA3 to contribute significantly to age-related bone loss and increased cytokine expression in the mouse. Some of the effects of SAA3 in aging are likely due to its ability to activate the NLRP3 inflammasome in macrophages and produce IL-1β. Future goals are to determine the receptors by which PGE2 acts to facilitate production of SAA3 in macrophages, the mechanisms involved in the SAA3 inflammasome activation, and the mechanisms by which SAA3 leads to cellular senescence in old mice.

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. – Her clinical focus is in the care of patients with endocrine neoplasms. These disorders include several subtypes of thyroid cancer. Since 2003, Dr. Tendler’s been an active participate in survivorship programs (ThyCa and AMEND). Patients with endocrine neoplasms may present with disorders that may be inherited found in more than one family member often called causing thyroid, adrenal, parathyroid, pituitary dysfunction in the setting of multiple endocrine neoplasia type 1 (MEN-1), multiple endocrine neoplasia type 2 (MEN-2), patients with medullary thyroid cancer (sporadic and in the setting of hereditary MEN-2), patients with pheochromocytomas, paraganlgiomas (SDH mutations, VHL mutations). She puts emphasis on planning long term surveillance and coordinating care plans for patient and family members who may be affected by these disorders. She created the website for the Connecticut Endocrine Society which includes links for patients. In addition, participate in the evaluation and treatment of patients with adrenal, parathyroid and pituitary disorders (sporadic and in the setting of hereditary subtypes often causing growth hormone excess or acromegaly or cortisol excess or Cushing’s). At our institution, we have experience with adrenal disorders include primary hyperaldosteronism, diagnosis and interpretation of adrenal vein sampling. Dr. Tendler collaborates with physicians in the medical community such as endocrine surgeons, neurosurgeons, radiation oncologists, and radiologists.

Liping Xiao, M.D., Ph.D., MSCTR – Dr. Xiao pursues basic research to elucidate the molecular mechanism(s) in sickle cell bone disease and 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. Dr.Xiao is a co-investigator who collaborates with Dr. Marja Hurley.