Osteoporosis is caused by the uncoupling of bone formation and bone resorption, resulting in low bone mass. Osteoporotic fractures are costly in terms of health care dollars and quality of life due to higher mortality and morbidity. Most osteoporosis therapies stabilize bone mass through inhibition of bone resorption; however, stimulation of bone formation may prove a more beneficial approach to reverse bone loss. A greater understanding of factors regulating the bone formation process holds promise for new therapeutics to treat osteoporosis and prevent bone loss. Recent studies have identified that global loss of Dedicator of cytokinesis 7 (Dock7), a guanine nucleotide exchange factor (GEF), in the spontaneous Dock7 mutant, the Misty mice, results in low bone mass with suppressed bone formation and accelerated bone resorption. Furthermore, preliminary data demonstrate that osteoblast precursors in Misty mice have defects in cell mobility, decreased cell migration and increased cell adhesion, as well as impaired osteogenic differentiation. Activation of small GTPases such as Rac1 and Cdc42, known targets of Dock7 as well as integral components of integrin and Wnt signaling pathways are important for modulators of osteoblast mobility and differentiation. Although the low bone mass phenotype observed in the Misty mice is in part due to higher sympathetic outflow, in vitro data support the working hypothesis that Dock7 is a critical regulator of osteoblast mobility and differentiation. In order to test that hypothesis, tw specific aims are proposed: (1) Define the role of Dock7 in controlling cell mobility and osteogenic differentiation of osteoblast precursors through modulation of small GTPase activation in integrin and Wnt signaling pathways; (2) Investigate the mechanism by which Dock7 controls bone remodeling in vivo through skeletal phenotyping of the conditional and global Dock7 knockout mice. By deleting Dock7 in mesenchymal stem cells using Prx1-Cre, the requirement for Dock7 in the formation of normal bone mass and coupling of bone remodeling can be assessed. The work proposed here will define the mechanism by which Dock7 regulates osteoblast differentiation and function and will provide new insights into potential therapeutic targets to combat osteoporosis. Through a combination of multidisciplinary mentoring, a thorough scientific investigation, utilizing primary in vitro culture and in vivo models, participaion in scientific meetings, focused instruction in manuscript and grant writing, and education on research ethics, these studies and the training plan will prepare the applicant for a nationally competitive and independent career in basic and translational bone biology research.
Osteoporosis resulting from uncoupled bone remodeling is a major health concern in the aging population. A greater understanding of the bone formation process will lead to therapies capable of stimulating bone formation and reversing bone loss. The aim of this study is to investigate the mechanism by which Dock7, a novel therapeutic target, promotes bone formation and couples bone remodeling.
|Le, Phuong T; Bishop, Kathleen A; Maridas, David E et al. (2017) Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice. Bone 105:103-114|
|Bishop, Kathleen A; Harrington, Anne; Kouranova, Evguenia et al. (2016) CRISPR/Cas9-Mediated Insertion of loxP Sites in the Mouse Dock7 Gene Provides an Effective Alternative to Use of Targeted Embryonic Stem Cells. G3 (Bethesda) 6:2051-61|