Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice  

作　　者：Zhousheng Xiao Li Cao Micholas Dean Smith Hanxuan Li Wei Li Jeremy C.Smith Leigh Darryl Quarles 

机构地区：[1]Department of Medicine,University of Tennessee Health Science Center,Memphis,TN 38163,USA [2]UT/ORNL Center for Molecular Biophysics,Oak Ridge National Laboratory,Oak Ridge,TN 37830,USA [3]Department of Biochemistry and Cellular and Molecular Biology,The University of Tennessee-Knoxville,Knoxville,TN 37996-1939,USA [4]Department of Pharmaceutical Sciences,University of Tennessee Health Science Center,Memphis,TN 38163,USA

出　　处：《Bone Research》2023年第4期772-783,共12页骨研究（英文版）

基　　金：supported by National Institutes of Health(NIH),National Institute of Arthritis and Musculoskeletal and Skin Diseases(Grant RO1-AR071930);National Institute of Diabetes and Digestive and Kidney Diseases(Grant RO1 DK121132);supported by the Office of Science of the U.S.Department of Energy under Contract No.DE-AC05-00OR22725。

摘　　要：Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood.Here,we used mouse genetics,mechanical loading,and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts.We created and compared the skeletal phenotypes of control Pkd1^(flox/)+;Wwtr1^(flox/)+,Pkd1^(Oc-cKO),Wwtr1^(Oc-cKO),and Pkd1/Wwtr1^(Oc-cKO)mice to investigate genetic interactions.Consistent with an interaction between polycystins and Wwtr1 in bone in vivo,Pkd1/Wwtr1^(Oc-cKO)mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKOor Pkd1^(Oc-cKO)mice.Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Pkd1/Wwtr1^(Oc-cKO)mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Moreover,we found that Pkd1/Wwtr1^(Oc-cKO)mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of loadinduced mechanosensing gene expression compared to control mice.Finally,control mice treated with a small molecule mechanomimetic,MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control.In contrast,Pkd1/Wwtr1^(Oc-cKO)mice were resistant to the anabolic effects of MS2.These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.

关 键 词：MEC IMPAIRED ADDITIVE 

分 类 号：R68[医药卫生—骨科学]