Identification of a Bioactive Domain in Type II Collagen That Promotes Bone Repair via EGFR Signaling

ABSTRACT Fractures represent a significant clinical burden, and bone marrow mesenchymal stem cells (BMSCs)‐based therapy holds promise for bone repair, contingent upon directing transplanted cells toward osteogenesis. In pathological conditions such as osteoporosis, uncontrolled lineage commitment of BMSCs toward adipogenesis rather than osteogenesis exacerbates bone loss. Type II collagen (Col II) is a potent bioactive material known to promote osteogenic over adipogenic differentiation in BMSCs. However, the specific bioactivity domains within Col II (Type II collagen peptide markers, Col II PMs) responsible for this activity remain unidentified. To address this, we employ an integrated strategy combining bioinformatic analysis and in silico simulation to identify a specific bioactivity domain (GFPGTPGLPGVK) within Col II. This domain specifically directs BMSCs toward osteogenic differentiation while suppressing adipogenic commitment. It functions by efficiently binding to the epidermal growth factor receptor on BMSCs, which is associated with osteogenic differentiation, thereby activating downstream signaling cascades including the PI3K/AKT and MAPK pathways. Moreover, this domain synergistically enhances bone regeneration by increasing osteoblast activity and inhibiting osteoclast function. Our findings elucidate the structural and mechanistic basis for Col II's regulation of BMSCs fate, offering a targeted strategy for designing bone‑repair biomaterials and therapies for metabolic bone disorders.