Semaphorin 3A: A new player in bone remodeling

Abstract

Semaphorin 3A (Sema3A) is a protein identified originally as a diffusible axonal chemorepellent. Sema3A has multifunctional roles in embryonic development, immune regulation, vascularization, and oncogenesis. Bone remodeling consists of two phases: the removal of mineralized bone by osteoclasts and the formation of new bone by osteoblasts, and plays an essential role in skeletal diseases such as osteoporosis. Recent studies have shown that Sema3A is implicated in the regulation of osteoblastgenesis and osteoclastgenesis. Moreover, low bone mass in mice with specific knockout of Sema3A in the neurons indicates that Sema3A regulates bone remodeling indirectly. This review highlights recent advances on our understanding of the role of sema3A as a new player in the regulation of bone remodeling and proposes the potential of sema3A in the diagnosis and therapy of bone diseases.

Keywords: Semaphorin 3A; bone remodeling; osteoblast; osteoclast; sensory innervation.

Figure 1. Schematic presentation of the structure of semaphorins and the receptors. (A) The structure of emaphorins (class 1–7 and V). Semaphorins are cell surface or secreted glycoproteins characterized by an N-terminal Sema domain, which is essential for signaling, immunoglobin loop, thrombospondin domain, and glycophosphatidylinositol (GPI) anchor. Class 3 molecules are secreted proteins that are distinguished by a conserved basic domain at C-terminal. (B) Sema3A signals are mediated by the receptors neuropilin 1 and plexinA. The extracellular domain of plexin contains a signal sequence, a sema domain, plexin semaphoring integrin (PSI) domains, and Ig-like plexin transcription factors (IPT). The cytosolic domain of plexin contains two GTPase-activating protein (GAP) domains. Neuropilins contain two complement binding (CUB) domains, two coagulation factor domains (FV/VIII), and a Meprin, A5, Mu (MAM) domain. Sema3A binds to the CUB domains of neuropilin and induces the conformational change of plexin, leading to the activation of intracellular signaling.

Figure 2. Sema3A signaling in bone remodeling. (A) Sema3A-mediated regulation of osteoclastgenesis. Sema3A-Nrp1 axis inhibits PLCγ activation and calcium oscillation, leading to the inhibition of osteoclast differentiation. In addition, Sema3A-Nrp1 axis repels ostoclast precursor cells through affecting RhoA activation. (B) Sema3A-mediated regulation of osteoblastgenesis. Sema3A activates Rac1 and canonical Wnt signaling via FERM, RhoGEF, and pleckstrin domain-containing protein 2 (FARP2), leading to osteoblast differentiation.

Figure 3. Role of sensory nerves in bone remodeling may be mediated by Sema3A indirectly in mouse model. In Sema3A_neuron^−/− mice, the sensory innervations are low and this is correlated with low bone mass. Therefore, sema3A is important for nerve innervations in the bone.

Figure 4. The hypothetical balance between osteo-anabolic afferent sensory nerves and osteo-catabolic efferent sympathetic nerves. The sympathetic nervous system regulates osteo-catabolic (bone resorbing) response via β-adrenergic receptor-2 (Adrb2) in the bone cells, while sensory nerve system regulates osteo-anabolic (bone forming) response via unidentified receptors. The balance of these actions modulate bone remodeling.