Tendon Cells Root Into (Instead of Attach to) Humeral Bone Head via Fibrocartilage-Enthesis.
Tendon Cells Root Into (Instead of Attach to) Humeral Bone Head via Fibrocartilage-Enthesis.
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DOI：
10.7150/ijbs.79007
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发表时间：
2023
影响因子：
9.2
通讯作者：
Feng, Jian Q.
中科院分区：
文献类型：
--
作者：
Wang, Zheng;Ma, Chi;Chen, Diane;Haslett, Caitlin;Xu, Chunmei;Dong, Changchun;Wang, Xiaofang;Zheng, Minghao;Jing, Yan;Feng, Jian Q.
大关节由两个紧密相连的软骨组成：关节软骨（AC;富含II型胶原，一种研究充分的组织）和纤维软骨附着点（FE;富含I型胶原，附着点病和运动损伤的常见疾病部位，尽管很少受到关注）。多年来，这两种软骨都被认为是由软骨细胞形成的，而附着在肱骨头上的肌腱主要被认为是完全不同的结缔组织。在这项研究中，我们提出了一个非传统的假设：肌腱细胞直接通过细胞转分化形成FE。为了验证这一假设，我们首先定性和定量地证明了AC和FE在细胞形态和细胞分布、矿化状态、细胞外基质（ECM）含量和关键ECM蛋白表达谱方面的明显差异。接下来，我们使用ScxLin（肌腱特异性Cre ScxCreERT 2; R26 R-tdTomato系）在早期（P3）或年轻成年（P28）阶段用一次性他莫昔芬诱导追踪肌腱细胞的细胞命运，并分别收获不同发育年龄的小鼠。我们的早期跟踪数据显示，肌腱和FE不同的生长事件：最初的增加，但逐渐减少的ScxLin肌腱细胞和持续扩大的ScxLin FE细胞。年轻成人示踪数据表明，在P28和P56期间，ScxLin细胞持续募集到FE扩增中。一个单独的示踪系，3.2 Col 1 Lin（一种所谓的“骨特异性”系），进一步证实了肌腱细胞对FE细胞形成的直接贡献，这发生在几天内，但FE ECM成熟（包括高水平的SOST，一种有效的Wnt信号传导抑制剂）需要几周时间。最后，在ScxLin细胞中使用白喉毒素片段A（DTA）的功能丧失数据表明，肌腱和FE细胞中的ScxLin细胞显著减少，而功能获得研究（通过在P3一次性注射他莫昔芬稳定ScxLin肌腱细胞中的β-连环蛋白，并在P60收获）显示ScxLin肌腱和FE质量均显著扩增。总之，我们的研究表明，纤维软骨是一种入侵的附着点可能源于肌腱通过一个快速的细胞转分化机制与一个漫长的ECM成熟过程。出生后形成的纤维软骨扎根于现有的软骨中，牢固地连接肌腱和骨骼，而不是像人们普遍认为的那样作为简单的附着部位。我们相信，这项研究将刺激更激烈的探索，在这个欠研究的领域，特别是对病人的肌腱端病和运动损伤。
Large joints are composed of two closely linked cartilages: articular cartilage (AC; rich in type II collagen, a well-studied tissue) and fibrocartilaginous enthesis (FE; rich in type I collagen, common disorder sites of enthesopathy and sporting injuries, although receiving little attention). For many years, both cartilages were thought to be formed by chondrocytes, whereas tendon, which attaches to the humeral bone head, is primarily considered as a completely different connective tissue. In this study, we raised an unconventional hypothesis: tendon cells directly form FE via cell transdifferentiation. To test this hypothesis, we first qualitatively and quantitatively demonstrated distinct differences between AC and FE in cell morphology and cell distribution, mineralization status, extracellular matrix (ECM) contents, and critical ECM protein expression profiles using comprehensive approaches. Next, we traced the cell fate of tendon cells using ScxLin (a tendon specific Cre ScxCreERT2; R26R-tdTomato line) with one-time tamoxifen induction at early (P3) or young adult (P28) stages and harvested mice at different development ages, respectively. Our early tracing data revealed different growth events in tendon and FE: an initial increase but gradual decrease in the ScxLin tendon cells and a continuous expansion in the ScxLin FE cells. The young adult tracing data demonstrated continuous recruitment of ScxLin cells into FE expansion during P28 and P56. A separate tracing line, 3.2 Col 1Lin (a so-called "bone-specific" line), further confirmed the direct contribution of tendon cells for FE cell formation, which occurred in days but FE ECM maturation (including high levels of SOST, a potent Wnt signaling inhibitor) took weeks. Finally, loss of function data using diphtheria toxin fragment A (DTA) in ScxLin cells demonstrated a significant reduction of ScxLin cells in both tendons and FE cells, whereas the gain of function study (by stabilizing β-catenin in ScxLin tendon cells via one-time injection of tamoxifen at P3 and harvesting at P60) displayed great expansion of both ScxLin tendon and FE mass. Together, our studies demonstrated that fibrocartilage is an invaded enthesis likely originating from the tendon via a quick cell transdifferentiation mechanism with a lengthy ECM maturation process. The postnatally formed fibrocartilage roots into existing cartilage and firmly connects tendon and bone instead of acting as a simple attachment site as widely believed. We believe that this study will stimulate more intense exploring in this understudied area, especially for patients with enthesopathy and sporting injuries.
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