Endogenous Collagenases Regulate Osteoclast Fusion

The precise regulation of osteoclast differentiation and function is crucial for the maintenance of healthy bone. Despite several reports of collagenase expression in bone tissues, the precise isoform expression as well as the role in osteoclasts are still unclear. In the present report, the expression of matrix metalloprotease (MMP)8 and MMP13 was confirmed in mouse bone marrow macrophage osteoclast precursors. The mRNA and protein expressions of both collagenases were significantly reduced by receptor activator of nuclear factor κB ligand (RANKL) stimulation. Notably, either inhibition of MMP expression by siRNA or treatment of cells with collagenase inhibitor Ro 32-3555 significantly augmented osteoclast fusion and resorption activity without affecting the osteoclast number. The inhibition of collagenase by Ro 32-3555 increased the expression of osteoclast fusion genes, Atp6v0d2 and Dcstamp, without affecting nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) protein expression. The enhanced osteoclast fusion by collagenase inhibition appears to be mediated through an extracellular signal regulated kinase (ERK)-dependent pathway. Collectively, these data provide novel information on the regulation of osteoclast fusion process.