Novel roles of tendon during TMJ postnatal growth and onset of diseases

项目摘要 摘要颞下颌关节(TMJ)是人体最复杂的关节之一，发病率较高。 疾病和创伤。75%的儿童损伤后的TMJ可以在不手术的情况下再生 机制不明，而一些患者会出现强直，导致张口受限和 面部美观缺陷。TMJ由下颌骨、颞骨和关节盘组成，具有丰富的 肌腱附着物。肌腱被认为唯一的功能是将肌肉力量传递到 稳定关节，但在很大程度上还不清楚为什么肌腱在创伤或疾病中经历异位骨化，以及 它是否对骨骼的形成有任何直接的贡献。为了研究它的全部生物学意义 在TMJ生后生长和扩张过程中，进行了一系列体内实验。钥匙 研究结果是：a.颞下颌关节突由一个成熟的软骨头和一个被忽视的骨头骨组成。 它在出生后生长并在一生中不断扩大；b.附着肌腱的骨头骨、升支和 颞骨在矿物质形态、细胞形态和细胞外基质(ECM)方面具有独特的特征 与传统骨(如骨膜形成的骨，PFB)不同的轮廓；C.这一新的 已鉴定的骨组织(称为肌腱形成的骨，TFB)起源于SCX+(硬化症)肌腱细胞，通过 界面，并侵入邻近的软骨或骨骼，形成一种超越简单附着的紧密连接 D.低磷血症加速了细胞的增殖和转分化 无血管肌腱转移到TFB，导致TMJ畸形；以及E.成熟的SCX+肌腱细胞迅速而健壮 在TMJ创伤后，它们的命运转变为软骨和骨细胞，导致自我修复或强直。这些 新的发现提出了以下中心假设：肌腱细胞超越了它们在关节中的传统作用 运动，负责关节突头、升支和颞部的后天生长和扩张。 骨骼，以及在TMJ创伤修复和强直发作过程中的关键角色。为了验证这一假设，两个高度 相关而独立的具体目标被提出：1)确定肌腱在形成骨细胞中的新角色 在细胞形态上与常规骨不同的骨性髁头和骨支，细胞外基质 2)确定肌腱在TMJ颞骨生长过程中的新作用。 因为成人肌腱细胞的可塑性是导致创伤导致的TMJ强直的原因。在完成后 这项拟议的工作有望证明a)SCX+肌腱细胞对出生后的 TMJ骨头骨、升支和颞骨通过细胞转分化的生长和扩张 机制；以及b)成人肌腱细胞通过移位参与TMJ的修复和创伤后的强直 它们的细胞命运变成了软骨细胞和骨细胞。这项研究的发现将在很大程度上填补这方面的知识空白 未知但至关重要的领域，通过提高一种新型的肌腱衍生的骨来修改当前的教条，并为 为开发创伤和疾病中TMJ修复的新方法奠定基础。

Project Summary The Temporomandibular joint (TMJ) is one of the most complex joints in the human body, with high prevalence of diseases and trauma. 75% of the injured TMJ condyles in children can regenerate without surgery by an unknown mechanism, whereas some patients develop ankylosis, leading to restricted mouth opening and facial aesthetic defects. TMJ is composed of the mandibular condyle, temporal bone, and a disc with abundant tendon attachments. Tendon has been thought to play the sole function of transmitting muscle forces to stabilize joints, yet it is largely unclear why tendon undergoes ectopic ossification in trauma or diseases, and whether it has any direct contribution to skeletal formation. To investigate the full biological significance of tendon in TMJ postnatal growth and expansion, a series of in vivo experiments were performed. The key findings are a. the TMJ condyle is composed of a well-established cartilage head and an overlooked bony head that grows after birth and continuously expands during lifespan; b. the tendon-attached bony head, ramus, and temporal bone share unique features in mineral pattern, cell morphology, and ECM (extracellular matrix) profiles, which are distinct from conventional bone (such as periosteum-formed bone, PFB); c. this newly identified bone tissue (named tendon-formed bone, TFB) originates from Scx+ (scleraxis) tendon cells via an interface, and invades the adjacent cartilage or bone to form a tight connection beyond a simple attachment between tendon and bone; d. Hypophosphatemia accelerates cell proliferation and transdifferentiation of the avascular tendon to TFB, resulting in a malformed TMJ; and e. mature Scx+ tendon cells rapidly and robustly switch their fate to cartilage and bone cells upon TMJ trauma, giving rise to a self-repair or ankylosis. These novel findings raise the following central hypothesis: tendon cells, beyond their conventional role in joint movement, are responsible for the postnatal growth and expansion of TMJ condyle head, ramus, and temporal bone, as well as a key player during TMJ trauma repair and ankylosis onset. To test this hypothesis, two highly related, yet independent Specific Aims are proposed: 1) To define novel roles of tendon in forming bone cells of the bony condyle head and ramus, which are distinct from conventional bone in cell morphology, ECM components, and mineralization; 2) To define novel roles of tendon during TMJ temporal bone growth, as well as the plasticity of adult tendon cells that are responsible for trauma-induced TMJ ankylosis. Upon completion of the proposed work, it is expected to demonstrate that a) Scx+ tendon cells directly contribute to the postnatal growth and expansion of TMJ bony head, ramus, and temporal bone through a cell transdifferentiation mechanism; and b) adult tendon cells participate in TMJ repair and ankylosis onset upon trauma by shifting their cell fate to chondrocytes and bone cells. Findings from this study will fill knowledge gaps in this largely unknown but vital area, revise the current dogma by raising a new type of tendon-derived bone, and lay the foundation for developing novel approaches to the restoration of TMJ in trauma and disease.