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	Medical Page Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties. Chu K, Snyder R, Econs MJ. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. Asymptomatic gene carriers and clinically affected ADO2 subjects have the same CLCN7 mutation. We examined osteoclastic bone resorption in vitro as well as osteoclast formation, several markers, acid secretion, and cytoskeletal structure. We found that ADO2 expression results from osteoclast specific properties. INTRODUCTION: Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the CLCN7 gene. However, of those individuals with a CLCN7 mutation, one third are asymptomatic gene carriers who have no clinical, biochemical, or radiological manifestations. Disease severity in the remaining two thirds is highly variable. MATERIALS AND METHODS: Human peripheral blood mononuclear cells were isolated and differentiated into osteoclasts by stimulation with hRANKL and human macrophage-colony stimulating factor (hM-CSF). Study subjects were clinically affected subjects, unaffected gene carriers, and normal controls (n = 6 in each group). Pit formation, TRACP staining, RANKL dose response, osteoclast markers, acid secretion, F-actin ring, and integrin alpha(v)beta3 expression and co-localization were studied. RESULTS: Osteoclasts from clinically affected subjects had severely attenuated bone resorption compared with those from normal controls. However, osteoclasts from unaffected gene carriers displayed similar bone resorption to those from normal controls. In addition, the resorption lacunae from both unaffected gene carriers and normal controls appeared much earlier and spread much more rapidly than those from clinically affected subjects. As time progressed, the distinction between clinically affected subjects and the other two groups increased. No significant difference was found in acidic secretion or osteoclast formation between the three groups. Osteoclast cytoskeletal organization showed no difference between the three groups but there was low cellular motility in clinically affected subjects. CONCLUSIONS: Osteoclasts from the unaffected gene carriers, in contrast to those from the clinically affected subjects, functioned normally in cell culture. This finding supports the hypothesis that intrinsic osteoclast factors determine disease expression in ADO2. Further understanding of this mechanism is likely to lead to the development of new approaches to the treatment of clinically affected patients. PMID: 16813529 [PubMed - indexed for MEDLINE]		Scientific Advisors: Michael Econs, M.D., F.A.C.P., F.A.C.E., who directs the Division of Endocrinology and Metabolism, has used a combination of clinical and molecular research to substantially advance the field of metabolic bone disease. Contributions include identification of the genes responsible for X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemic rickets. He has also made contributions in understanding the genetics of osteoporosis and autosomal dominant osteopetrosis. He is on the editorial boards of both Endocrinology and The Journal of Clinical Endocrinology and Metabolism and is a member of the Central Society for Clinical Investigation and the American Society for Clinical Investigation. He is a highly sought after lecturer, speaking on various topics in metabolic bone disease at numerous academic institutions and medical/scientific meetings.  Gary E. Cordingley, M.D., Ph.D. Gary Cordingley graduated from Purdue University with a B.S. in chemistry and biology in 1971. He attended Duke University where he earned a Ph.D. in physiology and pharmacology in 1976, and an M.D. in 1977. He received internship training in internal medicine at the University of Michigan Hospitals 1977-1978, residency training in neurology at the Neurological Institute of Columbia-Presbyterian Medical Center in New York, 1978-1981, and fellowship training as a Pharmacology Research Associate in the National Institute of General Medical Sciences in Bethesda, Maryland, 1981-1983. He has practiced neurology in Athens, Ohio, since 1983. He is an associate professor of neurology at the Ohio University College of Osteopathic Medicine and a medical staff member of O'Bleness Memorial Hospital in Athens, Ohio. Dr. Cordingley has been certified in neurology by the American Board of Psychiatry and Neurology. He is a fellow of the American Academy of Neurology and a member of the American Headache Society. He is also a member of the Ohio Academy of Medical History and was president of this organization 1994-1997. In addition, he is the medicine and science advisor to the International Osteopetrosis Association. Dr. Cordingley's articles on neurology, neuroscience and medical history have appeared in numerous professional and general publications. L. Lyndon Key, MD Chairman, Department of Pediatrics Physician-in-Chief, MUSC Children's Hospital Dr. Lyndon Key joined the MUSC faculty as an associate professor in July 1991. He received his medical degree from the University of North Carolina in 1977 (AOA), completed a pediatrics residency at Duke University in 1980 and completed a clinical and research fellowship in endocrinology at Children's Hospital Boston and Harvard Medical School in 1983. Dr. Key was an instructor at Harvard Medical School for three years before joining the faculty of Wake Forest University where he served as the first division director of pediatric endocrinology and advanced to the rank of associate professor. During this time, Dr. Key began research programs in childhood bone diseases, growth hormone physiology and therapeutics, GnRH treatment of precocious puberty and the basic biology of bone resorption. In July 1991, Dr. Key joined MUSC to re-establish a pediatric endocrine division. He has developed a strongly funded research program and an outstanding clinical program. Initially appointed as an associate program director of the GCRC, he was named interim program director in December 1991. In 1993, Dr. Key was promoted to professor and program director of the GCRC. Dr. Key was instrumental in the re-funding of the GCRC in 1994 and in 2000. During his GCRC tenure, Dr. Key added an informatics core, a molecular core, and redesigned and enhanced clinical resources. In 1999, Dr. Key chaired a committee on the Future of Clinical Research at MUSC. As a result of this effort, Dr. Key was named assistant dean for clinical research. Dr. Key's osteopetrosis research led to the first FDA-approved therapy for this condition and headlined the NCRR Reporter in Spring 2000. Dr. Key has been a researcher in the area of bone and mineral metabolism, cytokine biology, and osteoclast physiology for 20 years. He has discovered the role of superoxide in bone resorption, the ability to use interferon gamma to alter white cell and osteoclast function in osteopetrosis, the role of calciriol in stimulation of bone resorption in humans. In addition, he is a National Advisor on Growth Hormone Therapy and its effect of bone density and growth. He is currently studying the effects of bisphosphonates in juvenile osteoporosis, the enzyme responsible for superoxide production in osteoclasts, and the ability of statins to limit neuroinflammation in multiple sclerosis. His new projects include an interest in derivation of islets from adult stem cells and the prolongation of islet cell viability with statins.