胫骨皮质横向牵张激活SSCs及HIF-1α/CXCL12/CXCR4通路对踝关节OA骨-软骨再生的作用及机制

踝关节骨关节炎(OA)是导致机体功能障碍的主要疾病，目前无有效疗法，主要病理特点是骨-软骨缺损且难以再生。团队前期临床研究以原创手术方案“胫骨皮质横向牵张”成功修复足部严重缺损的骨组织，同时发现该技术可促进踝关节OA骨-软骨缺损的修复。牵张成骨可激活局部骨骼干细胞(SSCs)及HIF-1α/CXCL12/CXCR4通路，介导骨再生。但SSCs是否参与胫骨皮质横向牵张介导的踝关节OA骨-软骨修复，尚未明确。我们将使用自发OA豚鼠并建立踝关节大块骨-软骨缺损模型，研究胫骨皮质横向牵张对踝关节OA骨-软骨的再生；并阐明髓腔、外周循环、踝关节OA骨-软骨中SSCs在该过程中的作用，同时明确SSCs是否通过HIF-1α/CXCL12/CXCR4通路的激活参与骨-软骨的再生。本项目将从动物、细胞和分子机制上明确胫骨皮质横向牵张促踝关节OA骨-软骨缺损再生的作用和机制，为踝关节OA的治疗提供新策略。

Ankle osteoarthritis (OA) is one of the major diseases leading to joint dysfunction. Currently there is no effective treatment for ankle OA. The pathogenesis of ankle OA is characterized by cartilage and subchondral bone defects which are difficult to repair or regenerate. In our previous clinical study, we treated patients who had severe bone defect in the feet using our original surgery protocol tibial cortex transverse distraction, and found that accompanying the regeneration of the defected bone, the regeneration of the osteochondral defects of the ankle OA occurred. Distraction osteogenesis activates the local skeletal stem cells (SSCs) and the HIF-1α/CXCL12/CXCR4 signaling pathway, resulting in abundant bone regeneration. However, whether SSCs plays a role in the tibial cortex transverse distraction-mediated regeneration of osteochondral defects in ankle OA remains largely unknown. We will first establish the animal model of Hartley guinea pig with spontaneous ankle OA and critical osteochondral defects, and then apply the tibial cortex transverse distraction. We will evaluate the effect of the tibial cortex transverse distraction on ankle OA osteochondral defect regeneration. Furthermore, we will assess the impact of the tibial cortex transverse distraction on the SSCs localized in bone marrow, circulation and ankle OA osteochondral defects, and clarify the role of the HIF-1α/CXCL12/CXCR4 pathway in the activation of SSCs. This project will clarify the mechanism by which tibial cortex transverse distraction mediates regeneration of ankle OA osteochondral defects at different levels and provide new strategies for ankle OA treatment.