Temporomandibular joint degeneration arises spontaneously in STR/ort mice and is prevented by targeted aggrecanase inhibition

Kazuhiro Ooi , Kazuhiro Yamamoto , Yutaka Kobayashi , Behzad Javaheri , Anders Jensen , Ioannis Kanakis , Takao Sakai , Fadi Jarad , Hiroyuki Nakamura , Andrew A. Pitsillides , Shuichi Kawashiri , George Bou-Gharios
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引用次数: 0

Abstract

Objective

Temporomandibular joint osteoarthritis (TMJ-OA) is painful and causes masticatory dysfunction, but current treatment is limited to symptom relief due to an incomplete appreciation of aetiology. Herein, we develop morphological and histological methods for quantitative evaluation of TMJ-OA severity and examine whether STR/Ort mice, which are genetically predisposed to spontaneous knee OA, exhibit protection against TMJ-OA upon genetic gain-of-function modification of an aggrecanase-selective mutant of tissue inhibitor of metalloproteinase (TIMP)-3.

Design

We established morphological changes in mandibular condylar head adapted from human TMJ-OA criteria, and developed and verified the utility of TMJ-OA histological damage scoring adapted from the OARSI system. Mutant TIMP3 containing an extra alanine at the N-Terminus ([-1A] TIMP-3 was overexpressed in STR/Ort and CBA mice. Morphological changes in mandibular condyle and TMJ cartilage degradation were evaluated and quantified using micro-CT and histology in mice aged 10, 20 and 40 weeks.

Results

Whilst no evidence of TMJ-OA was observed in STR/Ort mice aged 10 weeks, bone erosion and osteophyte formation appeared in the mandibular condyle by 20 weeks, with remarkable deformity and bone resorption at 40 weeks in STR/Ort, but not the parental CBA strain. TMJ-OA was less severe in 40 week-old [-1A]TIMP-3 overexpressing STR/Ort and CBA compared to wild-type mice.

Conclusions

Using our new mouse TMJ-OA scoring system we have found that OA affects joints other than the knee in the STR/Ort strain. Genetic gain-of-function modification of STR/Ort mice with an aggrecanase-selective mutant of tissue inhibitor of metalloproteinase (TIMP)-3 also affords in vivo chondroprotection against this TMJ-OA.
颞下颌关节退行性变在STR/ort小鼠中自发发生,可通过靶向聚集酶抑制来预防
目的颞下颌关节骨性关节炎(TMJ-OA)是一种疼痛且导致咀嚼功能障碍的疾病,但由于对其病因的认识不完全,目前的治疗仅限于症状缓解。在此,我们开发了形态学和组织学方法来定量评估TMJ-OA的严重程度,并检查STR/Ort小鼠是否在遗传上易患自发性膝关节炎,在金属蛋白酶组织抑制剂(TIMP)-3的聚合酶选择性突变体的遗传功能获得修饰后,表现出对TMJ-OA的保护作用。我们根据人类TMJ-OA标准建立了下颌髁头的形态学变化,并开发和验证了基于OARSI系统的TMJ-OA组织学损伤评分的实用性。在STR/Ort和CBA小鼠中,n端含有额外丙氨酸的突变体TIMP3 ([-1A] TIMP-3)过表达。采用显微ct和组织学方法对10、20、40周龄小鼠下颌髁突和TMJ软骨退化的形态学变化进行评价和量化。结果10周龄STR/Ort小鼠未见TMJ-OA, 20周龄STR/Ort小鼠下颌髁出现骨侵蚀和骨赘形成,40周龄STR/Ort小鼠出现明显的畸形和骨吸收,而亲本CBA小鼠无此现象。与野生型小鼠相比,40周龄[-1A]TIMP-3过表达STR/Ort和CBA小鼠的TMJ-OA程度较轻。结论使用我们新的小鼠TMJ-OA评分系统,我们发现在STR/Ort劳损中,OA影响的不是膝关节,而是其他关节。携带组织金属蛋白酶抑制剂(TIMP)-3聚集酶选择性突变体的STR/Ort小鼠的遗传功能获得修饰也可在体内对这种TMJ-OA提供软骨保护。
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来源期刊
Osteoarthritis and cartilage open
Osteoarthritis and cartilage open Orthopedics, Sports Medicine and Rehabilitation
CiteScore
3.30
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