Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation

Collagen XII, belonging to the fibril-associated collagens, is a homotrimeric secreted extracellular matrix (ECM) protein encoded by the COL12A1 gene. Mutations in the human COL12A1 gene cause an Ehlers-Danlos/myopathy overlap syndrome leading to skeletal abnormalities and muscle weakness. Here, we studied the role of collagen XII in joint pathophysiology by analyzing collagen XII deficient mice and human patients. We found that collagen XII is widely expressed across multiple connective tissue of the developing joint. Lack of collagen XII in mice destabilizes tendons and the femoral trochlear groove to induce patellar subluxation in the patellofemoral joint. These changes are associated with an ECM damage response in tendon and secondary quadriceps muscle degeneration. Moreover, patellar subluxation was also identified as a clinical feature of human patients with collagen XII deficiency. The results provide an explanation for joint hyperlaxity in mice and human patients with collagen XII deficiency. Examination of the single cell transcriptome in joints with collagen XII deficiencyXII型胶原蛋白（Collagen XII）隶属于原纤维相关胶原蛋白家族，是由COL12A1基因编码的同源三聚体分泌型细胞外基质（extracellular matrix, ECM）蛋白。人类COL12A1基因发生突变可引发埃勒斯-当洛斯综合征/肌病重叠综合征，临床表现为骨骼异常与肌无力。本研究通过分析XII型胶原蛋白缺陷小鼠及人类患者样本，探究了XII型胶原蛋白在关节病理生理过程中的作用。研究结果显示，XII型胶原蛋白在发育中关节的多种结缔组织内广泛表达。小鼠体内XII型胶原蛋白的缺失会破坏肌腱与股骨滑车沟的结构稳定性，进而诱发髌股关节的髌骨半脱位；该病变与肌腱的细胞外基质损伤应答及继发性股四头肌变性存在显著关联。此外，髌骨半脱位也被确认为XII型胶原蛋白缺陷人类患者的临床表型之一。本研究结果为XII型胶原蛋白缺陷小鼠及人类患者的关节过度松弛现象提供了合理的机制解释。本研究还对XII型胶原蛋白缺陷关节的单细胞转录组进行了检测分析。