Key Takeaways & Executive Findings
- •• Magnesium implants significantly enhance cortical bone thickening and osteogenesis compared to titanium implants in a mouse model. • Magnesium activates integrin α10β1, leading to upregulation of FAK/p-FAK and Wnt/β-catenin signaling, while suppressing MAPK signaling. • Integrin α10β1 expression positively correlates with osteogenic marker genes (Runx2, osterix, ALP, BSP), indicating its role in osteogenic differentiation. • Periosteal stem cells are the key cellular population mediating magnesium-induced bone formation, with magnesium promoting their proliferation and differentiation.
Abstract
BACKGROUND: Periosteal stem cells are the key cellular population in magnesium-induced osteogenesis. Integrin α10β1 is a magnesium-dependent heterodimeric adhesion molecule. Mg²⁺ binds to the MIDAS domain of integrin α10β1, functioning as a molecular switch to regulate downstream biological processes. OBJECTIVE: To elucidate the mechanism by which magnesium-based implants regulate osteogenic differentiation of periosteal stem cells by activating integrin α10β1. METHODS: Forty-two C57BL/6 mice were randomly divided into a titanium rod implantation group (n=21) and a magnesium rod implantation group (n=21). Titanium rods and magnesium rods were implanted into the medullary cavity of the intercondylar fossa of the left knee joint femur, respectively. Three days post-surgery, samples were collected for TUNEL staining to observe cell apoptosis around the implants. EdU staining was utilized to observe cell proliferation activity in the cortical bone thickening area. Fourteen days post-surgery, samples were collected for Micro-CT analysis of cortical bone thickening and osteogenesis. Hematoxylin-eosin staining was applied to observe the morphology of new bone in the thickened cortical bone area. Calcein double labeling was used to analyze osteogenic differentiation of periosteal stem cells. qPCR was performed to detect the expression of osteogenic marker genes Runx2, osterix, alkaline phosphatase, bone sialoprotein, integrin α10, and integrin β1. Western blot was used to detect the protein expression of integrin α10, integrin β1, focal adhesion kinase (FAK), phosphorylated FAK, and components of Wnt/β-catenin and mitogen-activated protein kinase (MAPK) signaling pathways. Transcriptome sequencing was conducted to analyze the correlation between integrin α10β1 and osteogenic gene expression. RESULTS AND CONCLUSION: (1) TUNEL and EdU staining showed that around the titanium rod, a large number of apoptotic cells accumulated, and only a few proliferating cells were observed in the periosteal region without osteogenic differentiation; around the magnesium rod, no apoptotic cells were detected, and proliferating cells in the thickened periosteal area were significantly increased. (2) Micro-CT analysis showed that the titanium rod was not degraded, while the magnesium rod degraded significantly; the magnesium rod group exhibited better cortical bone thickening and osteogenesis than the titanium rod group. Hematoxylin-eosin and calcein double labeling staining showed that the magnesium rod group had superior cortical bone thickening and osteogenesis compared to the titanium rod group. qPCR results showed that the mRNA expression of Runx2, osterix, alkaline phosphatase, bone sialoprotein, integrin α10, and integrin β1 was higher in the magnesium rod group than in the titanium rod group. Western blot results showed that the protein expression of integrin α10, integrin β1, FAK, phosphorylated FAK, and Wnt/β-catenin was higher in the magnesium rod group, while MAPK expression was lower. Transcriptome sequencing analysis revealed a significant positive correlation between integrin α10β1 and the expression of Runx2, osterix, alkaline phosphatase, and bone sialoprotein. (3) These findings indicate that magnesium-based implants promote osteogenic differentiation of periosteal stem cells by activating the integrin α10β1-FAK/p-FAK signaling pathway, upregulating Wnt/β-catenin signaling, and inhibiting part of the MAPK signaling.
1. Introduction
With the aging population, the incidence of osteogenic disorders such as age-related osteoporosis, traumatic fractures, bone defects, and femoral head necrosis has been increasing annually. Current clinical treatments primarily involve surgical implantation of bone fixation and repair materials [1]. However, existing materials have limitations, including stress shielding effects, release of toxic metal ions, limited sources, or immune rejection, leading to suboptimal clinical outcomes [2-4]. Recent studies have demonstrated that magnesium and its alloys possess excellent biocompatibility, biodegradability, and osteogenic activity, overcoming the drawbacks of conventional bone repair materials. Consequently, magnesium-based materials have attracted considerable attention in biomaterials and orthopedic applications and are regarded as promising next-generation orthopedic implant materials [5-7].
Previous research has reported that magnesium induces cortical bone thickening and osteogenesis in rats, and this osteogenic behavior is periosteum-dependent, with new bone formation primarily originating from periosteal stem cells [8]. Periosteal stem cells are a cell population with high proliferative, migratory, and osteogenic potential. They possess core characteristics of skeletal stem cells and express gene sets related to stem cell properties and limb or skeletal system development, with regenerative potential even superior to bone marrow stem cells [9-10]. Early studies have shown that integrin α10β1 is distributed in the periosteum [11] and is also expressed in cells within the Ranvier groove (a structure involved in bone development), which contains chondrocytes and osteoblast precursors involved in bone growth and development.
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YANG Yanjun, ZHU Lin, GU Yongchun, YAN Zhanjun (2026). Mechanism by which magnesium implant-activated integrin α10β1 promotes osteogenic differentiation of periosteal stem cells. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21542
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Frequently Asked Questions
What is the role of integrin α10β1 in magnesium-induced osteogenesis?
Integrin α10β1 is a magnesium-dependent adhesion molecule that binds Mg²⁺ via its MIDAS domain, acting as a molecular switch to activate downstream signaling pathways, including FAK/p-FAK and Wnt/β-catenin, which promote osteogenic differentiation of periosteal stem cells.
How does magnesium promote bone formation compared to titanium?
Magnesium implants degrade and release Mg²⁺, which activates integrin α10β1 on periosteal stem cells, leading to enhanced proliferation and osteogenic differentiation. In contrast, titanium implants are inert and do not stimulate this pathway, resulting in less new bone formation.
What are the key signaling pathways involved in magnesium-induced osteogenesis?
The study shows that magnesium activates the integrin α10β1-FAK/p-FAK pathway, upregulates Wnt/β-catenin signaling, and inhibits part of the MAPK signaling, collectively promoting osteogenic differentiation of periosteal stem cells.
Why are periosteal stem cells important for bone regeneration?
Periosteal stem cells are a key cell population with high proliferative and osteogenic potential. They are responsible for cortical bone formation and repair, and their regenerative capacity is superior to bone marrow stem cells, making them crucial for bone regeneration.
What are the clinical implications of this study?
The findings suggest that magnesium-based implants could be a promising alternative to traditional titanium implants for bone repair, especially in conditions like osteoporosis and bone defects, by enhancing osteogenic differentiation through integrin α10β1 activation.
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