Bone-Specific Overexpression of PITX1 Induces Senile Osteoporosis in Mice Through Deficient Self-Renewal of Mesenchymal Progenitors and Wnt Pathway Inhibition

The cellular and molecular mechanisms underlying senile osteoporosisremain poorly understood. In this study, transgenic mCol1α1-Pitx1 miceoverexpressing paired-like homeodomain 1 (PITX1), a homeobox transcriptionfactor, rapidly develop a severe type-II osteoporotic phenotype withsignificant reduction in bone mass and biomechanical strength similar to thatseen in humans and reminiscent of the phenotype previously observed in Sca-1(Ly6a)-null mice. PITX1 plays a critical role in hind limb formation duringfetal development, while loss of expression is associated with primary knee/hiposteoarthritis in aging humans. Through in vivo and in vitro analyses, wedemonstrate that Pitx1 directly regulates the self-renewal of mesenchymalprogenitors and indirectly regulates osteoclast differentiation through theupregulation of Wnt signaling inhibitors DKK1, SOST, and GSK3-β. This isconfirmed by elevated levels of plasma DKK1 and the accumulation ofphospho-β-catenin in transgenic mice osteoblasts. Furthermore, overexpressedPitx1 in mice osteoblasts results in severe repression of Sca-1 (Ly6a) that waspreviously associated with senile osteoporosis. Our study is the first todemonstrate the novel roles of PITX1 in senile osteoporosis where PITX1regulates the self-renewal of mesenchymal stem cells or progenitor cells throughSca-1 (Ly6a) repression and, in addition, inhibits the Wnt signaling pathway.