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

Ooi, Kazuhiro
; 
Yamamoto, Kazuhiro
; 
Kobayashi, Yutaka
; 
Javaheri, Behzad
; 
Jensen, Anders
; 
Kanakis, Ioannis
; 
Sakai, Takao
; 
Jarad, Fadi
; 
Nakamura, Hiroyuki
; 
Pitsillides, Andrew A.
... show 2 more
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Affiliation
Kanazawa University; University of Liverpool; Royal Veterinary College; University of Chester; Fujita Health University; Ryukyu University
EPub Date
Publication Date
2025-03-11
Submitted Date
Collections
Chester Medical School
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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.
Citation
Ooi, K., Yamamoto, K., Kobayashi, Y., Javaheri, B., Jensen, A., Kanakis, I., Sakai, T., Jarad, F., Nakamura, H., Pitsillides, A. A., Kawashiri, S., & Bou-Gharios, G. (2025). Temporomandibular joint degeneration arises spontaneously in STR/Ort mice and is prevented by targeted aggrecanase inhibition. Osteoarthritis and Cartilage Open, 7(2), article-number 100599. https://doi.org/10.1016/j.ocarto.2025.100599
Publisher
Elsevier
Journal
Osteoarthritis and Cartilage Open
Research Unit
URI
http://hdl.handle.net/10034/629320
DOI
10.1016/j.ocarto.2025.100599
PubMed ID
PubMed Central ID
Type
Article
Language
en
Description
© 2025 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International (OARSI).
Series/Report no.
ISSN
EISSN
2665-9131
ISBN
ISMN
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Sponsors
Versus Arthritis Career Development Fellowship; Grant(s): 21447 to K.Y. Versus Arthritis Bridging Fellowship; Grant(s): 23137 to K.Y. Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research; Grant(s): 18K09764 to K.O, 21K10135 to K.O
Additional Links
https://www.sciencedirect.com/science/article/pii/S2665913125000354