Inhibition of osteoclastogenesis by ectodomain shedding of M-CSF receptor

Masahiro Hiasa,*^, ** Masahiro Abe,* Kenzo Asaoka,** Toshio Matsumoto*

Department of Medicine and Bioregulatory Sciences*,

Department of Biomaterials and Bioengineering**,

Institute of Health Biosciences, The University of Tokushima Graduate School

　Monocytes are a common precursor for both osteoclasts (OC) and dendritic cells (DC). However, regulatory mechanisms of monocytic differentiation into OC and DC are largely unknown. Because GM-CSF and IL-4 potently induce DC and suppress OC formation in the presence of M-CSF and RANKL, the present study was undertaken to clarify the mechanism of triggering deflection of OC and DC differentiation, by focusing on the effect of GM-CSF and IL-4 on M-CSF signaling.　GM-CSF and IL-4 potently down-regulated cell-surface M-CSFR on monocytes and up-regulated soluble form of M-CSFR. TNF-a converting enzyme (TACE) is the most up-regulated sheddase after the GM-CSF and IL-4 treatment. Interestingly, TAPI-0, a TACE inhibitor, abrogated the M-CSFR ectodomain shedding enhanced by GM-CSF and IL-4, and resumed OC formation. These observations demonstrate that GM-CSF and IL-4 up-regulate TACE in monocytes, which cleaves membrane-bound M-CSFR to disrupt M-CSF signaling and regulate OC/DC differentiation.