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 TAZ have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of controlPkd1flox/+;TAZflox/+, singlePkd1Oc-cKO, singleTAZOc-cKO, and doublePkd1/TAZOc-cKOmice to investigate genetic interactions. Consistent with an interaction between polycystins and TAZ in bonein vivo, doublePkd1/TAZOc-cKOmice exhibited greater reductions of BMD and periosteal MAR than either singleTAZOc-cKOorPkd1Oc-cKOmice. 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 doublePkd1/TAZOc-cKOmice compared to either singlePkd1Oc-cKOorTAZOc-cKOmice. DoublePkd1/TAZOc-cKOmice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to singlePkd1Oc-cKOorTAZOc-cKOmice. Moreover, we found that doublePkd1/TAZOc-cKOmice exhibited impaired responses to tibia mechanical loadingin vivoand attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic MS2 had marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, doublePkd1/TAZOc-cKOmice were resistant to the anabolic effects of MS2 that activates the polycystin signaling complex. These findings suggest that PC1 and TAZ form an anabolic mechanotransduction signaling complex that responds to mechanical loading and serve as a potential novel therapeutic target for treating osteoporosis.