Role and mechanism of Integrin α5β1 in bone formation and disease

Abstract

Integrin α5β1 is a key signaling protein between cells and the extracellular matrix. It plays crucial roles in biological processes such as cell adhesion, migration, and differentiation. Recent studies have shown that integrin α5β1 is significantly involved in bone formation and related diseases. Integrin α5β1 participates in the differentiation of mesenchymal stem cells into osteoblasts. It interacts with the CCN family and the bone morphogenetic protein pathway to upregulate the expression of osteogenic markers, promoting the formation of mineralization nodules. Additionally, it can mediate mechanical force stimulation to upregulate osteogenic gene expression and promote bone formation. In diseases such as osteoporosis, osteoarthritis, and bone metastasis, integrin α5β1 mediates abnormal cell-matrix adhesion and migration, promoting pathological bone resorption and inhibiting bone formation, thereby exacerbating bone loss. Therefore, integrin α5β1 may be a potential therapeutic target for these bone diseases. Elucidating its mechanism of action will help understand the homeostatic regulation of bone metabolism and provide ideas for the development of novel therapeutic strategies for skeletal diseases.

Keywords: bone formation; bone metastasis; integrin α5β1; osteoarthritis; osteoporosis.

FIGURE 1

Integrin α5β1 bidirectional signaling pathway diagram. In the “outside-in” signaling pathway, integrin α5β1 binds to ligands such as ECM, activating downstream signaling pathways through molecules like FAK and Src, such as MAPK and PI3K. This regulates cell survival, proliferation, adhesion, and migration, as well as extracellular matrix assembly. In the “inside-out” signaling mechanism, integrin α5β1 activation promotes the regulation of interactions between cells and the ECM. Intracellular calcium levels, PKC, TGF-β signals, and key proteins such as Talin and Kindlin bind to the β1 tail of integrin, activating the conformational change of integrin α5β1 (figure generated through BioRender.com).

FIGURE 2

Osteogenesis is regulated by integrin α5β1. This process begins with mesenchymal stromal cells (MSCs) differentiating into pre-osteoblasts, which then mature into fully functional osteoblasts. Throughout this progression, α5β1 is indispensable for promoting osteoblast adhesion, lineage specification, and responsiveness to the extracellular matrix. Mature osteoblasts secrete bone matrix proteins to drive new bone formation and, upon completing their anabolic functions, undergo programmed apoptosis. Specifically, α5β1 binding to RGD-containing ECM ligands facilitates osteoblast adhesion and migration. Osteogenesis is further modulated by fibroblast growth factors, bone morphogenetic proteins, hormones, ECM composition, and mechanical cues—all of which converge on α5β1 regulation to fine-tune bone formation (figure generated through BioRender.com).

FIGURE 3

Integrin α5β1 mediates common pathological mechanisms in both osteoarthritis and bone metastasis. In osteoarthritis, cartilage matrix damage generates inflammatory cytokines, matrix metalloproteinases, and fibronectin fragments, which degrade collagen. Fibronectin fragments bind α5β1 and TLRs, activating NF-κB and MAPK signaling to provoke further release of inflammatory mediators and MMPs, driving extensive matrix breakdown. Concurrently, α5β1 engagement on immune cells induces IL-1β, TNF-α, and MMP expression, exacerbating synovial inflammation and cartilage degradation. This same α5β1-driven axis operates in bone metastasis, accelerating tumor-induced bone destruction (figure generated through BioRender.com).