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

肌腱在颞下颌关节出生后生长和疾病发生过程中的新作用

• 批准号: 10445200
• 负责人: Yan Jing
• 金额: $ 35.98万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-11 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445200
• 关键词: Adult; Animal Model; Ankylosis; Area; Biological; Birth; Bone Growth; Bone Spur; Bone Tissue; Buffers; Cartilage; Cell Proliferation; Cells; Cellular Morphology; Child; Chondrocytes; Complex; Defect; Degenerative Disorder; Diagnosis; Disease; Epiphysial cartilage; Esthetics; Extracellular Matrix; Extracellular Matrix Proteins; Face; Female; Foundations; Goals; Growth; Head; Heterotopic Ossification; High Prevalence; Human body; Hypophosphatemia; Ice; Injury; Invaded; Joint repair; Joints; Knowledge; Longevity; Mandibular Condyle; Minerals; Muscle; Myofascial Pain Syndromes; Names; Natural regeneration; Onset of illness; Operative Surgical Procedures; Oral cavity; Osteogenesis; Pain management; Patients; Pattern; Periosteum; Phosphorus; Physical therapy; Play; Population; Practice Management; Research; Research Proposals; Rest; Role; Series; Site; Source; TMD treatment; Temporal bone structure; Temporomandibular Joint; Temporomandibular Joint Disorders; Tendon structure; Testing; Tissues; Trauma; Work; arthropathies; base; bone; bone cell; cartilage cell; cell type; craniofacial bone; experimental study; imaging modality; in vivo; injured; insight; joint formation; joint injury; joint mobilization; mechanical force; mineralization; novel; novel strategies; postnatal; repaired; restoration; scleraxis; skeletal; skeletal disorder; transdifferentiation; treatment strategy

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.

项目摘要 颞下颌关节（Temporomandibular joint，TMJ）是人体最复杂的关节之一，发病率高 疾病和创伤。75%的儿童颞下颌关节髁状突损伤可以通过非手术方式再生， 机制不明，而一些患者发展为关节强直，导致张口受限， 面部美学缺陷颞下颌关节由下颌髁状突、颞骨和一个具有丰富 肌腱附着肌腱一直被认为是唯一的功能，传递肌肉力量， 稳定关节，但很大程度上不清楚为什么肌腱在创伤或疾病中发生异位骨化， 是否对骨骼的形成有直接的作用为了研究 肌腱在生后TMJ生长和扩张中的作用，进行了一系列的在体实验。关键 调查结果是A。颞下颌关节髁状突是由一个明确的软骨头和一个被忽视的骨头组成的 在出生后生长并在寿命期间持续扩大; B.肌腱附着的骨头、支和 颞骨在矿物质模式、细胞形态和ECM（细胞外基质）方面具有独特特征 轮廓，其不同于常规骨（例如骨膜形成骨，PFB）; c.这个新 经鉴定的骨组织（称为腱形成骨，TFB）来源于Scx+（巩膜轴）腱细胞，通过 界面，并侵入相邻的软骨或骨，以形成超出简单附着的紧密连接 在肌腱和骨之间; d.低磷酸盐血症促进了细胞增殖和转分化， TFB的无血管肌腱，导致TMJ畸形;以及e.成熟的Scx+肌腱细胞迅速和稳健地 在TMJ创伤后，将它们的命运转变为软骨和骨细胞，从而引起自我修复或关节强直。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， 颞下颌关节髁状突头、升支和颞下颌关节的生长和扩张与运动有关 骨，以及在颞下颌关节创伤修复和强直发作的关键球员。为了验证这一假设，两个高度 相关的，但独立的具体目的提出：1）确定新的作用，肌腱在形成骨细胞， 骨髁头和支，这是不同于传统的骨细胞形态，ECM 探讨肌腱在颞下颌关节颞骨生长过程中的作用， 成年肌腱细胞的可塑性是造成创伤性颞下颌关节强直的原因。完成后 这项工作的建议，预计将证明a）Scx+肌腱细胞直接有助于出生后 通过细胞转分化促进TMJ骨头、支和颞骨的生长和扩张 B）成年腱细胞通过移位参与创伤后TMJ修复和关节强直发作 它们的细胞命运是软骨细胞和骨细胞。这项研究的结果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，通过提出一种新型的肌腱衍生骨来修改当前的教条，并奠定 为开发创伤和疾病中颞下颌关节修复的新方法奠定了基础。