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This study focuses on the research of bone mechanisms related to osteoporotic fractures, aiming to identify potential bone-related targets for fracture prevention. The study adopts a proteomic range Mendelian randomization combined with co-localization research strategy to screen and identify 9 circulating proteins related to the risk of forearm fractures, including bone-related proteins targeted by osteoporosis treatment and new bone-related proteins. The feasibility of the research method has been verified. The study mainly identified ephrin-A1 as a novel fracture protective factor, which can bind to the high-affinity receptor EphA2 of osteoblasts. Experimental models and genetic analysis confirmed that ephrin-A1 can regulate bone density, suggesting its bone-related mechanism for mediating fracture protection. Through spatial expression analysis using 3D DeepBone technology, it was clarified that ephrin-A1 on the surface of endothelial cells interacts spatially with EphA2 on osteoblasts on the bone surface. In summary, this study established ephrin-A1–EphA2 signaling as a potential bone-related target for bone strengthening and reducing fracture risk. This review addresses the regenerative and repair challenges caused by the heterogeneity of bone-cartilage tissue, with a tissue engineering system combining mesenchymal stem cells and biomaterial scaffolds as the core. It elucidates the regulatory mechanism of biological physical signals on the fate of stem cells, systematically summarizes the progress in the design of biomimetic microenvironment scaffolds under mechanical biology guidance, and achieves precise regulation of mesenchymal stem cell lineage differentiation, providing theoretical support and design references for layered bone-cartilage regeneration, especially the regeneration of subchondral bone. Firstly, through the method of proteome-wide Mendelian randomization combined with colocalization analysis, the circulating proteins related to the risk of forearm fractures were screened out; secondly, the membrane-associated protein ephrin-A1 was identified as a novel fracture protection factor, and the binding relationship between it and the high-affinity receptor EphA2 of osteoblasts was clarified; subsequently, the regulatory effect of ephrin-A1 on bone density was verified using experimental models and genetic analysis, and the bone-related mechanism mediated by this pathway for fracture protection was revealed; finally, the spatial interaction pattern of ephrin-A1 and EphA2 in bone tissue was analyzed by the 3D DeepBone technology, and ephrin-A1–EphA2 signal transduction was established as a potential bone-related target for bone strengthening and fracture risk reduction.
03 Research Design
This study adopted a multi-dimensional and multi-technology combined research design, specifically divided into three core stages: 1. Target screening stage: Using proteome-wide Mendelian randomization (MR) method combined with colocalization analysis, the entire range of circulating protein groups was screened to identify proteins related to the risk of forearm fractures; 2. Function verification stage: Constructing bone-related experimental models and conducting genetic analysis to verify the bone-related function of the candidate protein ephrin-A1 and its interaction with EphA2; 3. Spatial localization analysis stage: Utilizing the innovative 3D DeepBone technology to conduct spatial expression analysis of bone tissue, clarifying the spatial interaction positions of ephrin-A1 and EphA2, and completing the bone-related target research system from screening to verification and positioning.
04 Results
1. Target screening results: Through proteome-wide Mendelian randomization combined with colocalization analysis, 9 circulating proteins related to the risk of forearm fractures were successfully identified, including existing bone-related proteins targeted by osteoporosis treatment, and 3 new bone-related proteins were discovered, verifying the feasibility of the MR analysis process in this study. 2. New protective factor identification results: The study identified ephrin-A1 as a fracture protection factor, which is a membrane-associated protein released into the circulation and can specifically bind to the high-affinity receptor EphA2 of osteoblasts. 3. Bone density regulation results: The results of bone-related experimental models and genetic analysis indicated that ephrin-A1 can regulate bone density, suggesting that this protein mediates the bone-related mechanism of fracture protection. 4. Spatial interaction results: Using 3D DeepBone technology for spatial expression analysis, the spatial interaction positions of ephrin-A1 on the endothelial cell surface and EphA2 on adjacent osteoblasts in the bone surface were clarified, providing spatial-level evidence for the bone-related mechanism of this signaling pathway. 5. Core conclusion results: Based on the above analysis, ephrin-A1–EphA2 signal transduction was established as a potential bone-related target for bone strengthening and fracture risk reduction.
05 Extension of Ideas
1. In-depth exploration of mechanisms: Further analysis can be conducted to explore the specific regulatory mechanisms of ephrin-A1–EphA2 signaling pathway in different physiological stages of bone metabolism (such as bone formation and bone resorption), and clarify the molecular pathways of this signaling pathway regulating bone density. 2. Expansion of disease scenarios: The study can be extended to different bone-related diseases (such as osteoporosis, bone defects, osteoarthritis), to explore the differences in the roles of ephrin-A1–EphA2 signaling pathway in the occurrence and development of different bone diseases. 3. Pathway Interaction Study: Analyze the interaction between the ephrin-A1–EphA2 signaling pathway and other known bone metabolism pathways (such as the Wnt/β-catenin pathway, the TGF-β pathway), to reveal the network mechanism of bone metabolism regulation. 4. Target Function Verification: Through in vitro and in vivo bone tissue models, deeply verify the specific effects of this signaling pathway on the functions of bone cells (osteoblasts, osteoclasts), and improve the functional annotation of bone-related targets.
Original source:
1. Journal: Nature Communications
2. Publication Date: February 21, 2026
3. DOI: 10.1038/s41467-026-69863-6
4. Authors: Sofia Movérare-Skrtic, Maria Nethander, Lei Li, Nelson Tsz Long Chu, Ostap Dregval, Xin Tian, Karin H. Nilsson, Petra Henning, Ulf H. Lerner, Andrei S. Chagin, Claes Ohlsson
