Molecular Musculoskeletal

 

Dr. Hesham Tawfeek
VA RR&D National Center of Excellence
for the Medical Consequences of Spinal Cord Injury
Jame J. Peters VAMC, Bronx, New York
(718) 584-9000 x
heshamA.tawfeek@va.gov

In 1992, Dr. Tawfeek received his MBBCh degree (Bachelor of Medicine, Bachelor of Surgery) after six years of academic work at El-Minia University Faculty of Medicine, Egypt. Before becoming a physician at Tambdy Hospital in El-Minia, Dr. Tawfeek completed his clinical training as a House Officer at El-Minia University Hospital. Discovering his interests in basic laboratory research, Dr. Tawfeek joined the Endocrine Unit at Massachusetts General Hospital as a Research Assistant in 1997. Through his work there and as a Research Fellow in Medicine two years later at Massachusetts General Hospital and Harvard Medical School, Dr. Tawfeek received extensive training in basic scientific investigation.

Dr. Tawfeek studied subcellular localization of the receptor for the parathyroid hormone or PTH, a protein hormone that is important for maintaining the calcium level of blood, and the relevance of PTH receptor localization to receptor function and calcium regulation and bone health. His studies are critical for understanding disorders of bone and mineral-metabolism and for developing new approaches to treat these disorders. In 1998, he received the prestigious Young Investigator Award from the American Society for Bone and Mineral Research.

In 2002, after completing his fellowship, Dr. Tawfeek spent the next 7 years as an Instructor in Medicine for Harvard Medical School and an Assistant in Biology at Massachusetts General Hospital. In 2009, he joined the Endocrine Division at Emory University as an Instructor of Medicine to continue his studies on bone metabolism. The interactions between the skeletal and immune systems, and how this interaction related to parathyroid hormone and estrogen actions on bone, were of intense interest to Dr. Tawfeek.

In 2011, Dr. Tawfeek joined the Department of Orthopedic Surgery at Columbia University, where he worked for 3 years in an independent research program to generate genetic and pharmacologic tools for bone research. While at Columbia, he supervised and mentored five undergraduate, graduate and postgraduate investigators.
What brought him to his current position in the Spinal Cord Damage Research Center position is his strong interest in bone physiology and his ability to apply his knowledge of “designer” drugs to improve bone metabolism after spinal cord injury. His current research interests are to determine the mechanisms responsible for bone loss in patients with a spinal cord injury and to develop more efficient pharmacological approaches that will prevent bone loss after acute spinal cord injury or restore bone mass and integrity after chronic spinal cord injury.

Project goals (Lay)
The decrease in bone strength due to loss of bone substance, or osteoporosis, is more commonly appreciated by most medical professionals in postmenopausal women and in older persons. Osteoporosis weakens bone and makes it more susceptible to fracture after falls or other trauma. Those with a spinal cord injury have excessive loss of bone over the first several years after their acute injury and then have progressive bone loss thereafter; severe bone deterioration results in a greatly increased risk of fracture, even to minor trauma. It should be mentioned that because of innovative rehabilitation medicine interventions, such as exoskeleton-assisted walking devices, the skeleton below the level of spinal cord injury must be strong enough to tolerate the stresses and strains of forces placed upon it by upright posture and walking without resulting in fracture.

Dr. Tawfeek has been investigating the interactions between the cells of the skeletal and immune system and how the parathyroid hormone and its subcellular PTHR1 receptor are relevant in calcium regulation and bone health. The interactions between the skeletal and immune system and the effect of estrogen on bone mass are also areas of interest. The development of efficient pharmacological approaches to maintain bone homeostasis in persons after an acute spinal cord injury and to restore bone mass in those who have lost bone are the long-range objectives of his work. The ultimate goal of this work is to improve the health and quality of life of persons with spinal cord injury.

Project goals (Scientific)
Dr. Tawfeek studies at MGH were the first to visually demonstrate internalization of parathyroid hormone (PTH) receptor 1 (PTHR1) and its subcellular localization. His findings further uncovered the mechanisms involved in the process of PTHR1 internalization and the biological relevance of this process. The impact of these findings was confirmed when he participated in developing a phosphorylation-deficient (PD) PTHR1 mouse model that exhibited sustained cAMP and calcium responses to PTH and increased bone mass. His research has major implications in the area of PTHR1 and calcium regulation and revealed important information that could be important in understanding disorders of mineral metabolism, bone diseases, and in designing drugs that could treat these disorders. Moreover, his demonstration of signaling cross-talk down-stream of PTHR1 could help explain the consequences of genetic, pharmacologic, or natural (disease mutations) alteration of important cellular molecules.
His research at Emory determined that PTH activation of PTHR1 in T cells was required for continuous PTH infusion and hyperparathyroidism to cause bone loss. The studies revealed that blocking PTHR1 signaling in T cells abrogates the capacity of PTH to stimulate osteoclast formation and induce bone loss. The results further showed that stimulation of PTHR1 in T cells increases the secretion of the osteoclastogenic cytokine TNF, a factor that promotes osteoclast differentiation and bone resorption both directly, and by regulating CD40/CD40 ligand axis in osteoblasts and T cells. Dr. Tawfeek’s role was also instrumental to the investigations of T cell roles in PTH bone anabolic response and estrogen-deficiency-induced bone loss and the role of antigen presenting cells and T cell co-stimulation in PTH actions on bone remodeling. These novel findings greatly advanced our understanding of the interaction between bone and the immune system, opened new avenues for understanding diseases of bone loss, and implicated the importance of considering the immune system in bone health and bone drug design.

At Columbia, Dr. Tawfeek was designing and screening a large number of PTH and PTH related peptide (PTHrP) compounds for favorable selective properties, bio-potency and potential side effects. The project led to the discovery of multiple novel peptide derivatives with distinct signaling properties that differentially regulate bone mass. This recent development will pave the way for improving bone anabolic, or “bone-building,” therapies for osteoporosis and other diseases associated with bone loss; this work will also pave the way to more successfully designer drugs to control calcium and phosphate homeostasis. In 2014, these compounds were filed for a provisional patent.
The contributions of Dr. Tawfeek to PTH receptor signaling and bone and T cell biology have provided insight into our general understanding of skeletal physiology and disease, and they have provided new potential strategies for the treatment of diseases that result in excessive bone loss.


 

Research

Relevant Publications

  1. Tawfeek HA, Che J, Qian F, Abou-Samra AB.  Parathyroid hormone receptor internalization is independent of protein kinase A and phospholipase C activation.  Am J Physiol Endocrinol Metab. 2001;281(3)E545-57. PMID:11500310

http://www.ncbi.nlm.nih.gov/pubmed/11500310

  1. Tawfeek HA, Qian F, Abou-Samra AB.  Phosphorylation of the receptor for parathyroid hormone and parathyroid hormone-related peptide is required for internalization and regulates receptor signaling.  Mol Endocrinol. 2002;16(1)1-13. PMID:11773434

http://www.ncbi.nlm.nih.gov/pubmed/11773434

  1. Tawfeek HA, Abou-Samra AB. Important role for the V-type H(+)-ATPase and the Golgi apparatus in the recycling of PTH/PTHrP receptor. Am J Physiol Endocrinol Metab. 2004;286(5):E704-10. PMID:15102616

http://www.ncbi.nlm.nih.gov/pubmed/15102616

  1. Bounoutas GS, Tawfeek HA, Frolich LF, Chung UI, Abou-Samra AB.  Impact of impaired receptor internalization on calcium homeostasis in knock-in mice expressing a phosphorylation-deficient parathyroid hormone (pth)/pth-related peptide receptor. Endocrinology. 2006 ;147(10):4674-9 PMID:16840548

http://www.ncbi.nlm.nih.gov/pubmed/16840548

  1. Tawfeek HA, Abou-Samra AB. Negative regulation of PTH-activated phospholipase C signaling by PTH/PTHrP receptor phosphorylation and Protein Kinase A. Endocrinology. 2008;149(8):4016-23. PMID: 18450967

http://www.ncbi.nlm.nih.gov/pubmed/18450967

  1. Tawfeek HA, Bedi B, Li JY, Adams J, Kobayashi T, Weitzmann MN, Kronenberg HM, Pacifici R . Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PloS One. 2010; 20;5(8). PMID: 20808842

http://www.ncbi.nlm.nih.gov/pubmed/20808842

  1. Jau-Yi Li, Tawfeek H, Bedi B, Yang X, Adams J, Gao K, Zayzafoon M, Weitzmann MN, Pacifici R. Ovariectomy disregulates osteoblast and osteoclast formation through the T cell receptor CD40 ligand. Proc Natl Acad Sci U S A. 2011; 108(2):768-73. PMID: 21187391

http://www.ncbi.nlm.nih.gov/pubmed/21187391

  1. Tawfeek HA, Abou-Samra AB. Disruption of Parathyroid Hormone and Parathyroid Hormone Related Peptide Receptor Phosphorylation Prolongs ERK1/2 MAPK Activation and Enhances c-fos Expression. Am J Physiol Endocrinol Metab. 2012; 302(11):E1363-72. PMID: 22414806

http://www.ncbi.nlm.nih.gov/pubmed/22414806

Oh DS, Kim YH, Ganbat D, Han MH, Lim P, Back JH, Lee FY, Tawfeek H. Bone marrow absorption and retention properties of engineered scaffolds with micro-channels and nano-pores for tissue engineering: a proof of concept. Ceramics International.  2013; 39(7):8401-8410 15.