Figure 1. Role of axonal guidance molecules in bone formation and resorption coupling.

Bone formation and resorption coupling is a process wherein osteoclastic bone resorption is followed by osteoblastic bone formation. For resorption, two classes of axon guidance molecules, SLITs (SLIT3) and semaphorins (SEMA3a), act together to fine-tune repulsive signals for osteoclast migration, while inhibiting differentiation and cell fusion. SLIT3 is produced by mature osteoclasts, whereas the critical bone actions of SEMA3a originate from nerves. These repulsive and inhibitory effects of SEMA3a and SLIT3 on osteoclasts are countered by netrin-1, another molecule originally identified for its role in axon guidance. Netrin-1 attracts osteoclasts and promotes their fusion. Additional molecular pathways controlling osteoclasts include ephrin/ephrin receptor tyrosine kinase (ephrin/EPH) signaling via cell contact between osteoblasts and osteoclasts, and the RANKL/RANK pathway for osteoclastogenesis. For bone formation, signals released from mineralized matrix, such as TGF-β and IGF-1, in combination with signals secreted by osteoclasts, such as SLIT3, and those released by nerves, namely SEMA3a, serve in concert to recruit osteoblasts and promote their differentiation.