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

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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.