Bone Biology, Osteoporosis & Other Diseases of Bone

BIOGRAPHY

Joseph BidwellAcademic positions:Professor of Anatomy and Cell BiologyAll industry positions (in last five years): None declaredResearch interests: Ten million people in the US suffer from osteoporosis, a disease of reduced bone mass and debilitating fractures. Teriparatide (parathyroid hormone, PTH) is the only FDA-approved drug that replaces bone lost to osteoporosis. However, it is not the drug of first choice primarily due to cost. A cost-effective strategy for delivering teriparatide should include developing shorter courses of treatment that yield similar efficacy as longer-term therapy. Moreover, this might alleviate concerns over tachyphylaxis, where extended use of PTH results in diminished benefits. A weight-bearing exercise program may maximize teriparatide potency and clinical utility since combining PTH with mechanical loading synergizes bone growth in rodents. Identifying signaling pathways that regulate the response of the skeleton to both stimuli may be key to maximizing the impact of either stimulus alone or to mimicking the effects of both stimuli via pharmacologic targeting.The transcriptional repressor Nmp4/CIZ (nuclear matrix protein 4/cas interacting zinc finger protein) is a PTH-responsive and mechanically-responsive architectural transcription factor (ATF) that inhibits bone-anabolic genes. ATFs regulate gene activity by bending DNA. Disabling Nmp4/CIZ in mice enhances PTH-mediated gains in trabecular bone without compromising gains in cortical bone. Additionally, Nmp4/CIZ-null mice are immune to disuse-induced bone loss. Thus, inhibiting Nmp4/CIZ in patients may abbreviate and/or enhance teriparatide therapy, provide a prophylactic to disuse osteoporosis, and enhance the anabolic tonic derived from exercise. Our primary research focus is to determine how Nmp4/CIZ regulates bone response to PTH and/or changes in load. Nmp4/CIZ suppresses osteoid synthesis by repressing transcription of bone matrix genes. It is also found in the cytoplasm and binds to mechanosensitive focal adhesion proteins. Therefore, it may transduce PTH- or load-stimulated changes in bone cell adhesion into alterations in DNA conformation and transcription. Our studies include the search for Nmp4/CIZ targets. Within this context we are presently focusing on the Wnt/beta-catenin/LEF1 and HMGB1/RAGE signaling pathways. These data will facilitate the development of strategies for enhancing teriparatide potency, reveal new targets in the anabolic pathway, and provide a more cost-effective anabolic therapy. Any other information: