Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.

Abstract

Axin1 is a negative regulator of β-catenin signaling and its role in osteoblast precursor cells remains undefined. In the present studies, we determined changes in postnatal bone growth by deletion of <i>Axin1</i> in osteoblast precursor cells and analyzed bone growth in newborn and postnatal <i>Axin1</i>^<i>Osx</i> mice and found that hypertrophic cartilage area was largely expanded in <i>Axin1</i>^<i>Osx</i> KO mice. A larger number of chondrocytes and unabsorbed cartilage matrix were found in the bone marrow cavity of <i>Axin1</i>^<i>Osx</i> KO mice. Osteoclast formation in metaphyseal and subchondral bone areas was significantly decreased, demonstrated by decreased TRAP-positive cell numbers, associated with reduction of MMP9- and cathepsin K-positive cell numbers in <i>Axin1</i>^<i>Osx</i> KO mice. OPG expression and the ratio of <i>Opg</i> to <i>Rankl</i> were significantly increased in osteoblasts of <i>Axin1</i>^<i>Osx</i> KO mice. Osteoclast formation in primary bone marrow derived microphage (BMM) cells was significantly decreased when BMM cells were cultured with conditioned media (CM) collected from osteoblasts derived from <i>Axin1</i>^<i>Osx</i> mice compared with BMM cells cultured with CM derived from WT mice. Thus, the loss of Axin1 in osteoblast precursor cells caused increased OPG and the decrease in osteoclast formation, leading to delayed bone growth in postnatal <i>Axin1</i>^<i>Osx</i> KO mice.