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Review
. 2023 Nov 23:11:1321151.
doi: 10.3389/fcell.2023.1321151. eCollection 2023.

The effects of semaphorin 3A in bone and cartilage metabolism: fundamental mechanism and clinical potential

KaiLe Wu  1   2   3   4 , Donghua Huang  1   2   3   4 , Xin Huang  1   2   3   4
Affiliations
Review

The effects of semaphorin 3A in bone and cartilage metabolism: fundamental mechanism and clinical potential

KaiLe Wu et al. Front Cell Dev Biol. .

Abstract

Semaphorin 3A (Sema3A) is a neuroinformatic protein molecule with widespread expression across various tissues and organs. Recent investigations have unveiled its pivotal role in the skeletal system, primarily through its binding interactions with two co-receptors, neuropilin-1 (Nrp-1) and members of the plexin family. Prior research has confirmed the expression of Sema3A and its receptors in both osteocytes and chondrocytes. Beyond its expression patterns, Sema3A plays a multifaceted role in regulating bone and cartilage metabolism via employing diverse signaling pathways. Additionally, it engages in collaborative interactions with the immune and nervous systems, contributing to the pathophysiological processes underlying a spectrum of bone and joint diseases. In this paper, we undertake a comprehensive review of recent research developments in this field. Our objective is to deepen the understanding of Sema3A within the context of skeletal physiology and pathology. Furthermore, we aim to furnish a valuable reference for potential therapeutic interventions in the realm of bone and joint diseases.

Keywords: bone; cartilage; metabolism; semaphorin 3A; tissue engineering.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic structure of Sema3A and its receptors. Sema3A is defined by a distinctive structural composition, commencing with the Sema domain, subsequently followed by the PSI domain, and augmented by an additional Ig-like domain. Plexin-A1 possesses a structural arrangement beginning with an N-terminal Sema domain, followed by PSI domains, along with IPT domains in its extracellular region. Within its intracellular domain, Plexin-A1 encompasses two discrete cytoplasmic GTPase-activating protein (GAP) domains. In contrast, Nrp-1 consists of a generous extracellular domain, a solitary transmembrane domain, and a brief cytoplasmic tail. The extracellular segment is characterized by two initial CUB domains, followed by two coagulation FV/FVIII homology domains, and concludes with a membrane-proximal MAM domain.
FIGURE 2
FIGURE 2
Sema3A promotes osteoblast differentiation. The Wnt/β-catenin signaling system has been linked to osteogenic differentiation in previous studies. In the absence of Wnt, β-catenin undergoes phosphorylation and subsequently becomes sequestered by the destruction complex, a molecular assembly comprising APC, GSK3, and Axin1. Ultimately, it is targeted for degradation by the proteasome. When Sema3A binds to Nrp-1 and Plexin-A1, it activates Rac 1 and the canonical Wnt signaling pathway. This interaction recruits Axin1, leading to the liberation of β-catenin from the cytoplasm when Wnt binds to frizzled. Thus, nuclear β-catenin engages the TCF/LEF complex to enhance osteoblast differentiation, which is an indispensable process in bone remodeling.
FIGURE 3
FIGURE 3
Sema3A inhibits osteoclast differentiation. The RANKL/RANK signaling pathway is required for osteoclast differentiation, and the Plexin A1-TREM2-DAP12 complex can activate ITAM signaling. After enlisting TRAF6, RANK further activates NF-B and takes it into the nucleus to start osteoclast-related genes. Calcium oscillation also plays a crucial role in osteoclast differentiation. In addition to competitively binding to Plexin-A1, Nrp-1 blocks ITAM signaling and calcium oscillations via Sema3A signaling, which in turn prevents osteoclast differentiation and function.
FIGURE 4
FIGURE 4
Direct and indirect roles of Sema3A in bone homeostasis. Both directly and indirectly, sema3A, a crucial regulator in the preservation of bone homeostasis, influences bone regeneration. On the one hand, Sema3A acts on bone cells to stimulate bone formation and inhibit bone resorption, thus directly regulating bone repair. On the other hand, via coordinating immunological, vascular, and neurological processes, Sema3A indirectly influences bone formation. In general, Sema3A may inhibit angiogenesis through Nrp-1, while promoting sensory neuron development and modulating macrophage polarization, which create an immune microenvironment conducive to bone repair.
FIGURE 5
FIGURE 5
Sema3A signaling in cartilage metabolism and diseases. Because cartilage tissue lacks vascular nerves, its normal metabolism cannot be separated from mechanical signaling. The perichondrium contains the majority of stem cells, and the naive chondrocytes that are close to the perichondrium’s surface gradually multiply and grow into a mature population of homologous chondrocytes. Healthy articular chondrocytes contain Sema3A, which inhibits PTH-R1 and controls chondrocyte proliferation while promoting chondrocyte growth and changing intracellular protein content. Diseases that impact cartilage structure, like rheumatoid arthritis and osteoarthritis, disrupt normal mechanistic signaling, which changes the level of Sema3A expression in the tissue.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. XH accquired the Zhejiang Provincial Natural Science Foundation of China (LY23H060010), and DH accquired the National Natural Science Foundation of China (82002333).