Abstract
The cellular and molecular mechanisms underlying senile osteoporosis remain poorly understood. In this study, transgenic mCol1α1-Pitx1 mice overexpressing paired-like homeodomain 1 (PITX1), a homeobox transcription factor, rapidly develop a severe type-II osteoporotic phenotype with significant reduction in bone mass and biomechanical strength similar to that seen in humans and reminiscent of the phenotype previously observed in Sca-1 (Ly6a)-null mice. PITX1 plays a critical role in hind limb formation during fetal development, while loss of expression is associated with primary knee/hip osteoarthritis in aging humans. Through in vivo and in vitro analyses, we demonstrate that Pitx1 directly regulates the self-renewal of mesenchymal progenitors and indirectly regulates osteoclast differentiation through the upregulation of Wnt signaling inhibitors DKK1, SOST, and GSK3-β. This is confirmed by elevated levels of plasma DKK1 and the accumulation of phospho-β-catenin in transgenic mice osteoblasts. Furthermore, overexpressed Pitx1 in mice osteoblasts results in severe repression of Sca-1 (Ly6a) that was previously associated with senile osteoporosis. Our study is the first to demonstrate the novel roles of PITX1 in senile osteoporosis where PITX1 regulates the self-renewal of mesenchymal stem cells or progenitor cells through Sca-1 (Ly6a) repression and, in addition, inhibits the Wnt signaling pathway.
Highlights
Mean proteoglycan content in transgenic growth plates was determined by measuring changes in safranin O color intensity using the Image J software
We show that transgenic mCol1α1-Pitx[1] mice exhibit a phenotype reminiscent to human-related osteoporosis with reduced bone mineral density (BMD) and increased susceptibility to fractures
Mice of line 30 exhibited the highest Pitx[1] expression levels (~5-fold compared to wild type mice), while transgenic lines 22, 42, and 51, displayed lower levels of Pitx[1] expression (~1.8 fold), compared to wild type mice
Summary
Mean proteoglycan content in transgenic growth plates was determined by measuring changes in safranin O color intensity using the Image J software. Since the partial loss-of-function of Pitx[1] causes an increase in bone formation and density, it is conceivable that its gain-of-function could have the opposite effect, possibly causing an osteoporotic-like phenotype. We show that transgenic mCol1α1-Pitx[1] mice exhibit a phenotype reminiscent to human-related (type-II) osteoporosis with reduced bone mineral density (BMD) and increased susceptibility to fractures. Unlike postmenopausal (type-I) osteoporosis that results from an imbalance towards bone resorption, mCol1α1-Pitx[1] mice have both decreased bone formation from an osteoprogenitor deficiency and decreased bone resorption as a consequence of the inhibition of the Wnt/β-catenin signaling pathway. The decrease in osteoprogenitors in mCol1α1-Pitx[1] adult mice is not directly due to defects in osteoblastogenesis but rather due to reduced self-renewal activity of multilineage mesenchymal progenitors. Our data suggest that Pitx[1] overexpression reduces the self-renewal of the mesenchymal stem cell population through the repression of Sca-1/Ly6a
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