Mechanisms of heterotopic ossification in TMJ

颞下颌关节异位骨化的机制

• 批准号: 10817359
• 负责人: Joohyun Lim
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-29 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817359
• 关键词: Adult; Affect; Age Years; Biomechanics; Cells; Data; Defect; Deformity; Delaware; Development; Disease; FKBP10 gene; Heterotopic Ossification; High Prevalence; Homeostasis; Hydroxylation; Impairment; Individual; Knowledge; Length; Mandibular Condyle; Masseter Muscle; Medial; Mus; Musculoskeletal; National Institute of Dental and Craniofacial Research; Operative Surgical Procedures; Osteogenesis; Pain; Pathogenicity; Population; Procollagen; Pterygoid Muscle; Research; Research Personnel; Research Proposals; Signal Transduction; Temporomandibular Joint; Temporomandibular Joint Disorders; Tendon structure; Testing; Therapeutic Intervention; Tissues; Treatment outcome; United States; United States National Institutes of Health; Width; Woman; bone; crosslink; improved outcome; intervertebral disk degeneration; jaw movement; men; middle age; negative affect; pharmacologic; postnatal; prevent; stem cells; tissue injury; transmission process

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.

颞下颌关节紊乱病 (TMJD) 是一种异质性疾病，其特征是剧烈疼痛，对咀嚼功能产生负面影响。在美国，颞下颌关节紊乱病影响着超过 1000 万人，主要是中年人（20-40 岁），其中女性患病率高于男性 (NIDCR)。颞下颌关节紊乱病的治疗结果差异很大，这可能是由于对潜在致病机制的了解存在差距。因此，更好地了解 TMJD 的主要影响因素和致病机制可能会显着改善治疗和/或手术干预后的结果。尽管椎间盘退变在 TMJD 中的作用已得到充分证实，但对 TMJD 中肌腱和腱骨插入受损的功能后果却知之甚少。最近的研究表明，肌腱和肌腱-骨插入发育的缺陷以及对这些组织产生负面影响的细胞信号传导失调可能会导致颞下颌关节畸形（Roberts et al., 2019）。下颌运动产生翼状肌和咬肌产生的生物力学力，这些生物力学力通过肌腱和腱骨插入传递并连接到下颌骨髁。我们的初步研究表明，由于 Fkbp10 缺陷导致端肽赖氨酰羟基化和交联受损，会诱导 TMJ 异位骨化 (HO)，并显着增加出生后小鼠下颌髁突的长度和宽度。此外，我们发现 Fkbp10 缺失会诱导肌腱和肌腱-骨插入处表达 aSMA 的异常细胞，同时导致 TMJ 内侧髁中异位骨形成的增加。初步数据还显示，TMJ 肌腱和肌腱骨插入处的 pSmad1/5 表达增强，表明 BMP 信号传导失调。基于这些初步数据，我们将检验以下假设：TMJ 肌腱中端肽赖氨酰羟基化的改变会导致 HO 和功能缺陷，这是由于表达 aSMA 的祖细胞的异常分化依赖于异常的 BMP 信号传导所致。具体来说，我们将（目标 1）确定受损的前胶原 I 端肽赖氨酰羟基化和交联在 TMJ 稳态中的功能后果，（目标 2）确定 Fkbp10 缺失是否会触发组织损伤并改变表达 aSMA 的祖细胞群，以及（目标 3）确定异常 BMP 信号传导的药物抑制是否可以预防 TMJ 中的 HO Fkbp10 缺陷小鼠。拟议的研究将为开发由研究者发起的竞争性 R01 或同等的 NIH 研究提案提供基础基础和额外的初步数据。