Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent toll-like receptors (TLRs) in a murine model of osteoarthritis.
OBJECTIVE
The aim of our study was to evaluate the role of cell-membrane expressed TLRs and the signaling molecule MyD88 in a murine model of OA induced by knee menisectomy (surgical partial removal of the medial meniscus [MNX]).


METHODS
OA was induced in 8-10weeks old C57Bl/6 wild-type (WT) female (n=7) mice and in knockout (KO) TLR-1 (n=7), -2 (n=8), -4 (n=9) -6 (n=5), MyD88 (n=8) mice by medial menisectomy, using the sham-operated contralateral knee as a control. Cartilage destruction and synovial inflammation were evaluated by knee joint histology using the OARSI scoring method. Apoptotic chondrocytes and cartilage metabolism (collagen II synthesis and MMP-mediated aggrecan degradation) were analyzed using immunohistochemistry.


RESULTS
Operated knees exhibited OA features at 8weeks post-surgery compared to sham-operated ones. In menisectomized TLR-1, -2, -4, and -6 deficient mice, cartilage lesions, synovial inflammation and cartilage metabolism were similar to that in operated WT mice. Accordingly, using the same approach, we found no significant protection in MyD88-deficient mice in terms of OA progression as compared to WT littermates.


CONCLUSIONS
Deficiency of TLRs or their signalling molecule MyD88 did not impact on the severity of experimental OA. Our results demonstrate that MyD88-dependent TLRs are not involved in this murine OA model. Moreover, the dispensable role of MyD88, which is also an adaptor for IL-1 receptor signaling, suggests that IL-1 is not a key mediator in the development of OA. This latter hypothesis is strengthened by the lack of efficiency of IL-1β antagonist in the treatment of OA.
DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé 05-5029, 1011 Lausanne, Switzerland.
Sonia
S
Nasi
INSERM, UMR-S 606, Hospital Lariboisière, 75010 Paris, France; University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, 75205 Paris, France.
Hang-Korng
HK
Ea
DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé 05-5029, 1011 Lausanne, Switzerland.
Véronique
V
Chobaz
University of Nijmegen, Nijmegen, The Netherlands.
Peter
P
van Lent
INSERM, UMR-S 606, Hospital Lariboisière, 75010 Paris, France; University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, 75205 Paris, France.
Frédéric
F
Lioté
DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé 05-5029, 1011 Lausanne, Switzerland.
Alexander
A
So
DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé 05-5029, 1011 Lausanne, Switzerland. Electronic address: Nathalie.Busso@chuv.ch.
Nathalie
N
Busso
D000818:Animals; D002356:Cartilage / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D007375:Interleukin-1 / Q000502:physiology; D007593:Joint Instability / Q000150:complications; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors
Cartilage degradation and metabolism; Chondrocytes apoptosis; Experimental osteoarthritis; MyD88; Synovial inflammation; TLRs