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 Axin1 in osteoblast precursor cells and analyzed bone growth in newborn and postnatal Axin1 ^Osx mice and found that hypertrophic cartilage area was largely expanded in Axin1 ^Osx KO mice. A larger number of chondrocytes and unabsorbed cartilage matrix were found in the bone marrow cavity of Axin1 ^Osx 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 Axin1 ^Osx KO mice. OPG expression and the ratio of Opg to Rankl were significantly increased in osteoblasts of Axin1 ^Osx 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 Axin1 ^Osx 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 Axin1 ^Osx KO mice.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(81973876)

Chinese Academy of Sciences (CAS)(QYZDB-SSW-JSC030)

Ministry of Education of the People’s Republic of China (Ministry of Education of China)(IRT1270)

Shanghai Municipal Health Bureau (Shanghai Municipal Public Health Bureau)(ZY (2018-2020)-CCCX-3003)

Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology)(2015RA4002)

Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology)