SCHOLARS@TAMU

My laboratory has been engaged in multiple areas of NIH-funded musculoskeletal research since 1996. We were the first to identify the non-steroidal gonadal inhibin hormones in regulating the hypothalamic-pituitary-gonadal-skeletal axis in mice, and the role of changes in inhibins that signal the onset of menopause (reproductive aging) to the onset of increasing bone turnover. We also demonstrated the anabolic effect of continual Inhibin exposure in normal mice and in bone repair. Our cellular focus on Inhibins and the related factor, Activin A revealed that Activin A suppresses local bone resorption through suppression of osteoclast formation, motility and survival. Our ongoing work is in the area of specific inhibin/betaglycan receptor interactions that mediate the effects on bone cells. We are also greatly interested in improving the low bone mass that we were the first to identify in both humans with Down Syndrome (DS) and in mouse models of DS as a low bone turnover disease. Our current NIH-funded research is working to identify the mechanisms of reduced fracture healing and compromised bone regeneration in Down Syndrome. We have demonstrated the efficacy of both PTH and SclAb in DS, and are now actively testing nutriceuticals to increase bone mass in mouse models of Down Syndrome. The limitations of using mouse models to study bone disease led us to our most recent and exciting endeavors in collaboration with TAMU experts in reproduction and embryo transfer technologies to develop a large platform model of bone disease, using sheep. We have generated the first large animal model of hypophosphatasia (HPP) via high efficiency gene editing of a knock-in point mutation in the ALPL gene, whose musculoskeletal and dental phenotypes are consistent with human HPP. We are now using this model to determine the etiology of mineralization deficiencies, muscle weakness and premature tooth loss by analysis of longitudinal biopsies and analysis of muscle, bone and dental specimens using CT, microCT, mechanical testing, immunohistochemistry, histomorphometry and ex vivo bone marrow cultures.