title: Physiological mechanisms and therapeutic potential of bone mechanosensing.
abstract: Skeletal loading is an important physiological regulator of bone mass. Theoretically, mechanical forces or administration of drugs that activate bone mechanosensors would be a novel treatment for osteoporotic disorders, particularly age-related osteoporosis and other bone loss caused by skeletal unloading. Uncertainty regarding the identity of the molecular targets that sense and transduce mechanical forces in bone, however, has limited the therapeutic exploitation of mechanosesning pathways to control bone mass. Recently, two evolutionally conserved mechanosensing pathways have been shown to function as "physical environment" sensors in cells of the osteoblasts lineage. Indeed, polycystin-1 (Pkd1, or PC1) and polycystin-2 (Pkd2, or PC2' or TRPP2), which form a flow sensing receptor channel complex, and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1), which responds to the extracellular matrix microenvironment act in concert to reciprocally regulate osteoblastogenesis and adipogenesis through co-activating Runx2 and a co-repressing PPARγ activities. Interactions of polycystins and TAZ with other putative mechanosensing mechanism, such as primary cilia, integrins and hemichannels, may create multifaceted mechanosensing networks in bone. Moreover, modulation of polycystins and TAZ interactions identify novel molecular targets to develop small molecules that mimic the effects of mechanical loading on bone.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38165, USA.
authors.forename: Zhousheng
authors.initials: Z
authors.lastname: Xiao
authors.forename: Leigh Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D001842:Bone and Bones / Q000502:physiology*; D002923:Cilia / Q000502:physiology; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D010006:Osteoblasts / Q000502:physiology; D010024:Osteoporosis / Q000209:etiology / Q000628:therapy; D050396:TRPP Cation Channels / Q000502:physiology; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D050396:TRPP Cation Channels