Michael T. Collins, M.D.

Tenure Track Investigator
Chief, Skeletal Clinical Studies Unit

NATIONAL INSTITUTES OF HEALTH
BUILDING 30, ROOM 228 MSC 4320 BETHESDA, MD20892-4320

Phone: (301) 496-4913
Fax: (301) 402-0824
E-mail: mc247k@nih.gov

Biographical Sketch

Dr. Collins is a native Washingtonian who started his university training in music at the Catholic University Ward School of Music in Washington, D.C. in 1975. He left music to follow his calling in medicine when he took preparatory coursework at the University of Maryland, College Park, from which he graduated in 1987. It was also during this period when he came to the NIH to work as a biologist in the laboratory of Dr. Larry Tamarkin, NIMH, whose research focused on neuroendocrine/immune interaction. Dr. Collins completed his medical training (1988-1992), internship, residency and chief residency in internal medicine (1992-1996) at the University of Baltimore in Baltimore, MD. During medical school he worked in the laboratory of Dr. Moon Shin whose lab studied neuroimmunology, and also spent several months in the laboratory of Dr. Hemmo Drexhage at Erasmus University, Rotterdam, Netherlands, as part of a Medical Student Research Training Program grant where he studied immune/endocrine interaction. During his residency, Dr. Collins worked in the laboratory of Dr. Robert Lash, whose investigations focused on thyroid stimulating hormone structure/function. Dr. Collins came to the NIH for training in endocrinology and metabolism (1995-1998), where he has since remained. In 1998 he joined Dr. Pamela Robey’s laboratory in the Craniofacial and Skeletal Diseases Branch (formerly the Bone Research Branch) of the NIDCR. In 1999 he was appointed a staff clinician, and in 2006 was appointed to a tenure track position as chief of the Skeletal Clinical Studies Unit. Broadly speaking, his group studies endocrine regulation of bone and mineral metabolism. This is accomplished through clinical and translational studies of several specific disorders of bone and mineral metabolism including fibrous dysplasia of bone/McCune-Albright syndrome, disorders of fibroblast growth factor-23 (FGF23) excess and deficiency, and hypoparathyroidi

Research Interests/Scientific Focus

The research interests of the Skeletal Clinical Studies Unit (SCSU) center around clinical and translational studies of several specific disorders of bone and mineral metabolism including fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS), disorders of FGF23 excess and deficiency, and hypoparathyroidism.

FD/MAS is caused by activating, somatic mutations in the protein Gs alpha, which is central in the signaling pathway of many G-protein coupled receptors. Almost all of the mutations in FD/MAS occur at the same R201 position, the specificity of which makes it an ideal candidate for molecular targeting. The most prominent clinical aspects of MAS are café-au-lait spots, precocious puberty, FD, growth hormone excess, hyperthyroidism, cortisol excess, cardiac malformation and dysfunction, hepatic dysfunction, and an ill-defined neuropsychiatric syndrome. Severity exists across a spectrum from neonatal lethality to a trivial, incidentally discovered finding.

Since 1998, the SCSU has had a clinical program in FD/MAS that has included an ongoing Natural History study (98-D-0145), as well as several completed clinical trials (alendronate treatment of FD - 98-D-0146, pegvisomant for the treatment of growth hormone excess - 01-D-0197, and letrozole for the treatment of precocious puberty - 00-D-0183).

An exciting and ongoing translational program involves the discovery of small molecules with activity at the mutated Gs alpha that cause FD/MAS. This is a collaborative effort with the NIH Molecular Libraries Program that involves a high throughput approach to screen the NIH small molecule library with assays developed in the SCSU. The ultimate goal of this program is to turn molecules with activity at the mutated Gs alpha into drugs to treat FD/MAS.

A second area of focus in the SCSU is studies in FGF23. This work grew out of our previous work in which we found that FGF23 is produced by FD tissue, is responsible for FD-associated hypophosphatemic rickets and osteomalacia, and that the normal physiologic source of FGF23 is normal bone cells (primarily osteocytes). The two main foci of investigation in the study of FGF23 are that of FGF23 processing and action. FGF23 circulates as an intact, hormonally active protein as well as inactive degradation products. There is evidence to suggest that processing of FGF23 from the active to the inactive forms is a regulated process, and that this process is important in the overall control of FGF23 action. This is an area we are actively investigating. In addition, we previously showed that FGF23 action required the presence and action of parathyroid hormone (PTH), and that medicinally-induced hypoparathyroidism could blunt the action of FGF23. To better understand this, and to offer a new treatment for diseases of FGF23 excess we are planning to initiate a study of cinacalcet for the treatment of FGF23 excess disorders.

As part of our interest in the role of Gs alpha in bone, as well as part of our interest in FGF23/PTH interaction, we are studying the disorder of PTH deficiency, hypoparathyroidism. Important unanswered questions are what is the effect of PTH deficiency and PTH replacement on bone? To investigate this we are conducting a study of the effects of PTH replacement treatment for hypoparathyroidism on bone. In addition to traditional measures of bone metabolism and bone densitometry, we are performing labeled iliac crest biopsies at baseline and various intervals of time on PTH replacement. This will not only help us to be reassured that PTH replacement at doses necessary to maintain blood calcium levels are safe for bone, but inform us about the overall effect of PTH deficiency and replacement on bone biology.

In addition to the aforementioned work, the Unit maintains a number of active collaborations with investigators both in the NIH intramural program, including the Undiagnosed Diseases Program, as well as with investigator across the US and around the world. We are particularly keen in seeing patients with rare disorders of bone and mineral metabolism. Using the resources of the NIH Clinical Center we are able to study these patients for the purpose of expanding our current understanding of bone and mineral metabolism, and are often able to offer these patients treatments based upon what we learn about their underlying diseases.

Selected Publications

1. Collins MT, Chebli C, Jones J, et al. Renal phosphate wasting infibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia. J Bone Miner Res. May 2001;16(5):806-813.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11341325
2. Akintoye SO, Chebli C, Booher S, et al. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab. Nov 2002;87(11):5104-5112.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12414879
3. Lee JS, FitzGibbon E, Butman JA, et al. Normal vision despite narrowing of the optic canal in fibrous dysplasia. N Engl J Med. Nov 21 2002;347(21):1670-1676.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12444181
4. Riminucci M, Collins MT, Fedarko NS, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. Sep 2003;112(5):683-692. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12952917
5. Gupta A, Winer K, Econs MJ, Marx SJ, Collins MT. FGF-23 is elevated by chronic hyperphosphatemia. J Clin Endocrinol Metab. Sep 2004;89(9):4489-4492.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15356053
6. Collins MT, Lindsay JR, Jain A, et al. Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D. J Bone Miner Res. Nov 2005;20(11):1944-1950.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16234967
7. Akintoye SO, Kelly MH, Brillante B, et al. Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome. J Clin Endocrinol Metab. Aug 2006;91(8):2960-2966.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16720661
8. Cutler CM, Lee JS, Butman JA, et al. Long-term outcome of optic nerve encasement and optic nerve decompression in patients with fibrous dysplasia: risk factors for blindness and safety of observation. Neurosurgery. Nov 2006;59(5):1011-1017; discussion 1017-1018.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17143235
9. Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT. Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study. J Clin Endocrinol Metab. Jun 2007;92(6):2100-2106.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17405850
10. Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT. Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res. Jun 2007;22(6):931-937. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17352646
11. Hart ES, Kelly MH, Brillante B, et al. Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome. J Bone Miner Res. Sep 2007;22(9):1468-1474.
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17501668
12. Khosravi A, Cutler CM, Kelly MH, et al. Determination of the elimination half-life of fibroblast growth factor-23. J Clin Endocrinol Metab. Jun 2007;92(6):2374-2377. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17374707
13. Celi FS, Coppotelli G, Chidakel A, et al. The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome. J Clin Endocrinol Metab. Jun 2008;93(6):2383-2389.
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18349068
14. Dumitrescu CE, Kelly MH, Khosravi A, et al. A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features. Osteoporos Int. Jul 2009;20(7):1273-1278.
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18489744
15. Andreopoulou P, Dumitrescu CE, Kelly MH, et al. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. J Bone Miner Res. Jun 2011;26(6):1295-1302.
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21611969

Clinical Trials

• 98-D-0145: Screening and natural history of patients with polyostotic fibrous dysplasia and the McCune-Albright Syndrome
• 01-D-0184: Evaluation and Treatment of Bone and Mineral Disorders
• 07-D-0016: Effects of PTH Replacement on Bone in Hypoparathyroidism