Mechanisms of heterotopic ossification in TMJ

Temporomandibular joint disorder (TMJD) is a heterogeneous disease which is characterized by severe pain that negatively affects masticatory function. In the United States, TMJDs affect over 10 million individuals predominantly in middle-aged adults (20-40 years-of-age) with a higher prevalence in women than in men (NIDCR). Treatment outcomes for TMJDs are highly variable which may be attributed to the gap in knowledge of the underlying pathogenic mechanisms. Hence, a better understanding of the major contributors and causative mechanisms in TMJD may significantly improve outcome following therapeutic and/or surgical intervention. Whereas the contribution of disc degeneration in TMJD is well established, the functional consequence of impaired tendon and tendon-bone insertion in TMJD is poorly understood. Recent studies have shown that defects in tendon and tendon-bone insertion development as well as dysregulated cell signaling that negatively affect these tissues can cause deformities in TMJ (Roberts et al., 2019). Jaw movement creates biomechanical forces that are generated by the pterygoid and masseter muscles which are transmitted across tendon and tendon-bone insertion and connect to the mandibular condyle. Our preliminary studies have shown that impaired telopeptide lysyl hydroxylation and cross-linking due to Fkbp10- deficiency induces heterotopic ossification (HO) in TMJ and substantially increases mandibular condyle length and width in postnatal mice. In addition, we found that Fkbp10 deletion induces aberrant aSMA-expressing cells in the tendon and tendon-bone insertion concomitant with an increase in ectopic bone formation in the medial condyle of TMJ. Preliminary data also showed enhanced pSmad1/5 expression in the tendon and tendon-bone insertion in TMJ, indicating dysregulated BMP signaling. Based on these preliminary data, we will test the hypothesis that alterations in telopeptide lysyl hydroxylation in tendons of TMJ causes HO and functional defects due to abnormal differentiation of aSMA-expressing progenitor cells that is dependent on aberrant BMP signaling. Specifically, we will (Aim 1) determine the functional consequence of impaired procollagen I telopeptide lysyl hydroxylation and cross-linking in TMJ homeostasis, (Aim 2) determine if Fkbp10 deletion triggers tissue injury and alters aSMA-expressing progenitor cell populations, and (Aim 3) determine if pharmacological inhibition of aberrant BMP signaling can prevent HO in TMJ of Fkbp10-deficient mice. The proposed studies will provide the foundational basis and additional preliminary data to develop a competitive investigator-initiated R01 or equivalent NIH research proposal.