biostudies-literatureIshii TNIDCR NIH HHSNIA NIH HHSOsteo Science FoundationNational Institute of Dental and Craniofacial ResearchNCI NIH HHSNational Institute on Aging1750-1756https://www.ebi.ac.uk/biostudies/studies/S-EPMC10273054biostudies-literatureUnknown27(12)Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti-coupling factors. Amongst formally known anti-coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane-bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1-MMP are all expressed on the surface of RANKL-primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1-MMP. When TACE and MT1-MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti-TACE-mAb inhibited sSema4D releasJournal of cellular and molecular medicineSoluble Sema4D cleaved from osteoclast precursors by TACE suppresses osteoblastogenesis.PMC10273054DE027851R01 DE029709R56 AG064003R15 CA249788DE028715R21 DE028715R15 DE027851DE029709AG064003333466R01 AG064003Wisitrasameewong WKanzaki HAlbassam APierrelus RKawai TShindo SMovila AKandalam UHeidari AKim JYRuiz-Torruella MMinond DIshii TNakamura SfalseSoluble Sema4D cleaved from osteoclast precursors by TACE suppresses osteoblastogenesis.Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti-coupling factors. Amongst formally known anti-coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane-bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1-MMP are all expressed on the surface of RANKL-primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1-MMP. When TACE and MT1-MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti-TACE-mAb inhibited sSema4D releas2023-01-01T00:00:00Z2023 Jun2025-04-18T20:36:38.178Z2025-04-07T08:34:37.018ZS-EPMC102730543717068710.1111/jcmm.17416