Sclerostin expression in trabecular bone is downregulated by osteoclasts

Area of Science:

• Bone Biology
• Skeletal Physiology
• Cell Signaling

Background:

• Trabecular bone exhibits high turnover, while cortical bone has low turnover, but the regulatory mechanisms remain unclear.
• Osteocytes secrete sclerostin, a Wnt/β-catenin signaling antagonist, inhibiting bone formation.
• Leukemia inhibitory factor (LIF) from osteoclasts is known to suppress sclerostin and promote bone formation.

Purpose of the Study:

• To investigate the role of osteoclasts in regulating sclerostin expression and bone turnover in trabecular bone.
• To elucidate the involvement of Leukemia inhibitory factor (LIF) and RANKL signaling in this process.

Main Methods:

• Utilized Sost reporter mice and C57BL/6 mice treated with anti-RANKL antibody.
• Analyzed Tnfsf11 heterozygous (Rankl+/-) mice.
• Examined gene and protein expression (sclerostin, LIF, β-catenin) in bone tissues and cultured osteoclasts.

Main Results:

• Osteoclasts were found to downregulate sclerostin expression in trabecular bone, promoting bone turnover.
• Anti-RANKL treatment reduced osteoclasts, LIF-positive cells, and increased sclerostin-positive cells, while decreasing β-catenin and bone formation.
• Rankl+/- mice showed decreased LIF, increased sclerostin, and reduced β-catenin and bone formation in trabecular bone.
• RANKL stimulation in cultured osteoclasts increased Lif mRNA expression.

Conclusions:

• Osteoclasts play a crucial role in promoting trabecular bone turnover by downregulating sclerostin expression.
• The RANKL-LIF signaling pathway mediates the suppression of sclerostin by osteoclasts, thereby influencing bone formation and turnover.