Suppression of bone formation by osteoclastic expression of semaphorin 4D

Regulation of bone remodeling requires a constant balance between bone resorption, insured by osteoclasts, and bone formation, led by osteoblasts. Communication between these two cell types is crucial for bone remodeling. The authors of this study [1] show that cells from the osteoclastic lineage express semaphorin 4D, previously shown to be an axon guidance protein, and which potently inhibits bone formation.

Semaphorin 4D binds to plexin B1, a receptor expressed by osteoblasts. This binding activates small GTPase RhoA and, subsequently, protein kinase Rock in osteoblasts. In turn, activation of this pathway inhibits IRS-1 phosphorylation, modulating the insulin-like-growth factor 1 (IGF-1) signaling pathway, affecting osteoblast differentiation, mobility, and bone formation. Notably, administration of semaphorin 4D-specific antibodies suppresses bone loss occurring in ovariectomized mice.

This study highlights the role of semaphor 4D in the osteoclast - osteoblast communication, its effect on bone formation, and its emergence as a new target for development of drugs that aim to increase bone formation.

1. Negishi-Koga T et al. Nat Med. 2011;17:1473-1480.