Polycystin-1 and Bone Mechanotransduction

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Polycystin-1 and Bone Mechanotransduction

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Title: Polycystin-1 and Bone Mechanotransduction
Author: Huang, Wei
Citation: Huang, Wei. 2012. Polycystin-1 and Bone Mechanotransduction. Doctoral dissertation, Harvard University.
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Abstract: Bone mechanotransduction is a fundamental process underlying the remarkable ability of bones to perceive surrounding physical cues and adapt their mass, structure and overall strength to their mechanical environment. Therefore, it is central to many aspects of bone biology and disease. The key to a mechanistic understanding of this process lies in better knowledge of critical signaling molecules that relay the mechanical information inside bone cells. In this thesis, we investigate the role of polycystin-1 (PC1), a proposed fluid flow sensor in kidney epithelial cells, in transducing mechanical signals in bone cells. Loss of PC1 in osteoblast lineage cells using osterix-Cre (Osx-Cre) causes mild osteopenia in mice with reduced calvarial and trabecular bone formation, and markedly attenuated anabolic bone formation responses to in vivo mechanical loading of long bones. Loss of PC1 in limb bud mesenchymal cells at an early stage causes mildly increased bone formation and a tendency to exhibit enhanced anabolic responses to in vivo mechanical loading of long bones. These findings suggest that PC1 has a complex role in different bone cell populations both during development and in bone mechanotransduction. PC1 has been shown to mediate tensile force-induced proliferation in osteoprogenitor cells (OPCs) in craniofacial sutures. To investigate the role of PC1 in periosteal osteoprogenitor mechanotransduction, we establish a shockwave-induced periosteum mechanical stress model. Shockwave treatment triggers dramatically increased cell proliferation, potent osteogenic activity, and intramembranous new bone formation in the periosteum. We show that loss of PC1 in periosteal cells (Prx1-Cre) does not affect periosteal mechanoresponsiveness to shockwave mechanical stress. These findings suggest that the role of PC1 in OPCs is likely tissue or force dependent. Fluid shear stress (FSS) in the lacunar-canalicular network is a major force element that osteocytes experience and respond to in vivo. To study the role of PC1 in FSS-mediated osteocyte/osteoblast mechanotransduction, we establish a laminar FSS system with custom-made flow chambers and a PC1-deficient osteoblast cell line. Our data show that PC1 is essential for regulation of FSS-induced initial \(Ca^{2+}\) influx in osteoblasts and mediates osteoblast FSS responses in a COX-2 and AP-1 independent manner.
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10307760
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