The overall objective of this Program Project (PP) is to determine the mechanisms underlying the regulation of bone fracture repair with the expectation that the knowledge gained in the mouse models to be studied will be translated into new therapies for fracture repair in Veterans and Military Personnel. Each project will focus on a mechanism(s) that we have identified in preliminary experiments to be central for the healing process. Project 1 will explore the role of insulin-like growth factor-I (IGF-I) in coordinating the communication between chondrocytes, osteoblasts, and osteoclasts during the sequential process of fracture healing, looking first at specific deletions of IGF-I and its receptor in these different cells to determine if and how such deletions alter fracture healing, then examining the signaling pathways that may underlie the communication between these cells during the healing process. Project 2 will examine the role of the calcium sensing receptor (CaSR) in the different skeletal cells, using much of the same approach as in project 1 examining tissue specific deletions of CaSR in chondrocytes, osteoblasts, and osteoclasts for their impact on fracture repair. Project 3 will explore the role of G proteins and wnt signaling in mediating the ability of parathyroid hormone (PTH) to facilitate fracture repair. Mouse models in which the inhibitory G protein (Gi) is itself inhibited by overexpression of pertussis toxin, and the wnt inhibitor sFRP4 is deleted in a bone cell specific fashion will be examined for their impact on fracture healing per se, and on the ability of PTH to promote fracture healing. The Bone Core will have a primary focus on providing the structural and mechanical analyses of the healing fractures by high resolution micro computed tomography, histomorphometry, FTIR, micro indentation, and four point bending for all three Program Projects (PP). Moreover, the Core is also developing methods to evaluate the micro vasculature, useful for a number of projects outside of bone, but that will also provide a new approach to the analysis of bone fracture repair. Dr. Bikle will be the PI, and Dr. Nissenson will be the Associate PI of the PP, acting as PI in Dr. Bikle's absence. The executive committee will be comprised of the 3 PIs of the projects plus the Core Director, Dr. Chang. All are members of the Endocrine Research Unit (ERU) sharing space and equipment in that Unit. Weekly laboratory meetings by each research group and weekly strategy meetings with all members of the ERU will ensure ready communication among all participants of the PP. An Advisory Committee consisting of local experts in bone biology along with our outside collaborators will provide external review of each project and the PP overall on an annual basis.

Public Health Relevance

The expeditious healing of fractures is an important clinical problem for Veteran's health because of the impact of a variety of illnesses affecting fracture repair that are common in the VA population including vascular insufficiency, diabetes mellitus, osteoporosis, and nutritional deficiencies such as vitamin D and calcium. The signaling pathways we propose to study are involved with and affected by a number of such clinical conditions. Determining which cells during the repair process are particularly dependent these signaling pathways for proper function is the first step toward targeted therapy seeking to beneficially manipulate these pathways to promote bone fracture repair.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IP1)
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Endocrinology B (ENDB)
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Veterans Affairs Medical Center San Francisco
San Francisco
United States
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Tian, Faming; Wang, Yongmei; Bikle, Daniel D (2018) IGF-1 signaling mediated cell-specific skeletal mechano-transduction. J Orthop Res 36:576-583
Santa Maria, Christian; Cheng, Zhiqiang; Li, Alfred et al. (2016) Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism. Semin Cell Dev Biol 49:11-23
Wang, Tao; Wang, Yongmei; Menendez, Alicia et al. (2015) Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing. J Bone Miner Res 30:1572-84
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