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（TMJD）是一种异质性疾病，其特征是严重的疼痛，并对咀嚼功能产生负面影响。在美国，TMJDs影响了超过1000万人，主要是中年人（20-40岁），女性的患病率高于男性（NIDCR）。TMJDs的治疗结果是高度可变的，这可能归因于对潜在致病机制的知识差距。因此，更好地了解TMJD的主要致病因素和致病机制可能会显著改善治疗和/或手术干预后的预后。虽然椎间盘退变在TMJD中的作用已经得到了很好的证实，但在TMJD中受损的肌腱和肌腱-骨插入的功能后果却知之甚少。最近的研究表明，肌腱和肌腱-骨插入发育缺陷以及对这些组织产生负面影响的细胞信号失调可导致TMJ畸形（Roberts et al., 2019）。下颌运动产生的生物力学力是由翼状肌和咬肌产生的，它们通过肌腱和肌腱-骨止点传递并连接到下颌髁。我们的初步研究表明，由于Fkbp10-缺乏导致的端肽乙酰基羟基化和交联受损可诱导TMJ异位骨化（HO），并显著增加出生后小鼠下颌髁的长度和宽度。此外，我们发现Fkbp10缺失诱导肌腱和肌腱-骨止点的异常asma表达细胞，同时增加TMJ内侧髁的异位骨形成。初步数据还显示，pSmad1/5在TMJ肌腱和肌腱-骨止点的表达增强，表明BMP信号失调。基于这些初步数据，我们将验证TMJ肌腱端肽赖基羟基化的改变导致HO和功能缺陷的假设，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。具体来说，我们将（目的1）确定前胶原I端肽酰化和交联受损对TMJ稳态的功能影响，（目的2）确定Fkbp10缺失是否触发组织损伤并改变表达asma的祖细胞群，（目的3）确定异常BMP信号的药理抑制是否可以预防Fkbp10缺陷小鼠TMJ中的HO。拟议的研究将提供基础基础和额外的初步数据，以制定具有竞争力的研究者发起的R01或同等的NIH研究提案。