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

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 control Pkd1(flox/+);TAZ(flox/+), single Pkd1(Oc-cKO), single TAZ(Oc-cKO), and double Pkd1/TAZ(Oc-cKO) mice to investigate genetic interactions. Consistent with an interaction between polycystins and TAZ in bone in vivo, double Pkd1/TAZ(Oc-cKO) mice exhibited greater reductions of BMD and periosteal MAR than either single TAZ(Oc-cKO) or 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 double Pkd1/TAZ(Oc-cKO) mice compared to either single Pkd1(Oc-cKO) or TAZ(Oc-cKO) mice. Double Pkd1/TAZ(Oc-cKO) mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to single Pkd1(Oc-cKO) or TAZ(Oc-cKO) mice. Moreover, we found that double Pkd1/TAZ(Oc-cKO) mice exhibited impaired responses to tibia mechanical loading in vivo and 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, double Pkd1/TAZ(Oc-cKO) mice 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.