Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA.
Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA; Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.
Bone. 2023 Jan;166:116600. doi: 10.1016/j.bone.2022.116600. Epub 2022 Nov 9.
Non-union fractures have considerable clinical and economic burdens and yet the underlying pathogenesis remains largely undetermined. The fracture healing process involves cellular differentiation, callus formation and remodeling, and implies the recruitment and differentiation of mesenchymal stem cells that are not fully characterized. C-X-C chemokine receptor 4 (CXCR4) and Insulin-like growth factor 1 receptor (IGF-1R) are expressed in the fracture callus, but their interactions still remain elusive. We hypothesized that the regulation of CXCR4 by IGF-1R signaling is essential to maintain the bone homeostasis and to promote fracture repair. By using a combination of in vivo and in vitro approaches, we found that conditional ablation of IGF-1R in osteochondroprogenitors led to defects in bone formation and mineralization that associated with altered expression of CXCR4 by a discrete population of endosteal cells. These defects were corrected by AMD3100 (a CXCR4 antagonist). Furthermore, we found that the inducible ablation of IGF-1R in osteochondroprogenitors led to fracture healing failure, that associated with an altered expression of CXCR4. In vivo AMD3100 treatment improved fracture healing and normalized CXCR4 expression. Moreover, we determined that these effects were mediated through the IGF-1R/Insulin receptor substrate 1 (IRS-1) signaling pathway. Taken together, our studies identified a novel population of endosteal cells that is functionally regulated through the modulation of CXCR4 by IGF-1R signaling, and such control is essential in bone homeostasis and fracture healing. Knowledge gained from these studies has the potential to accelerate the development of novel therapeutic interventions by targeting CXCR4 signaling to treat non-unions.
非愈合性骨折具有相当大的临床和经济负担，但潜在的发病机制仍在很大程度上尚未确定。骨折愈合过程涉及细胞分化、骨痂形成和重塑，并暗示招募和分化间充质干细胞，这些干细胞尚未得到充分表征。C-X-C 趋化因子受体 4（CXCR4）和胰岛素样生长因子 1 受体（IGF-1R）在骨折骨痂中表达，但它们的相互作用仍然难以捉摸。我们假设 IGF-1R 信号对 CXCR4 的调节对于维持骨稳态和促进骨折修复至关重要。通过使用体内和体外相结合的方法，我们发现骨软骨祖细胞中 IGF-1R 的条件性缺失导致骨形成和矿化缺陷，这与特定群体的骨内膜细胞中 CXCR4 的表达改变有关。这些缺陷通过 AMD3100（CXCR4 拮抗剂）得到纠正。此外，我们发现骨软骨祖细胞中 IGF-1R 的诱导性缺失导致骨折愈合失败，这与 CXCR4 的表达改变有关。体内 AMD3100 治疗可改善骨折愈合并使 CXCR4 表达正常化。此外，我们确定这些作用是通过 IGF-1R/胰岛素受体底物 1（IRS-1）信号通路介导的。总之，我们的研究确定了一个新的骨内膜细胞群体，该群体通过 IGF-1R 信号对 CXCR4 的调节在功能上受到调节，这种控制对于骨稳态和骨折愈合至关重要。从这些研究中获得的知识有可能通过靶向 CXCR4 信号来治疗非愈合性骨折，从而加速新型治疗干预措施的开发。
