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

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.