High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis

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• 作者：W. de Munter^&dagger ; ; ^{Wouter.deMunter@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; M.H. van den Bosch^&dagger ; ; ^{Martijn.vandenBosch@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; A.W. Slö ; etjes^&dagger ; ; ^{Annet.Sloetjes@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; K.J. Croce^&Dagger ; ; ^{KCroce@partners.org" class="auth_mail" title="E-mail the corresponding author} ; T. Vogl^&sect ; ; ^{Vogl@uni-muenster.de" class="auth_mail" title="E-mail the corresponding author} ; J. Roth^&sect ; ; ^{RothJ@uni-muenster.de" class="auth_mail" title="E-mail the corresponding author} ; M.I. Koenders^&dagger ; ; ^{Marije.Koenders@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; F.A. van de Loo^&dagger ; ; ^{Fons.vandeLoo@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; W.B. van den Berg^&dagger ; ; ^{Wim.vandenBerg@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; P.M. van der Kraan^&dagger ; ; ^{Peter.vanderKraan@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author} ; P.L. van Lent^&dagger ; ; ^{Peter.vanLent@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cholesterol ; Low density lipoprotein ; S100A8 ; S100A9 ; Inflammation ; Osteophytes
• 刊名：Osteoarthritis and Cartilage
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：24
• 期：5
• 页码：844-855
• 全文大小：2906 K

文摘

A relation between osteoarthritis (OA) and increased cholesterol levels is apparent. In the present study we investigate OA pathology in apolipoprotein E (ApoE)^−/− mice with and without a cholesterol-rich diet, a model for high systemic low density lipoprotein (LDL) cholesterol levels independent of weight.

Method

Wild type (WT), Apoe^−/−, S100a9^−/− and Apoe^−/−S100a9^−/− mice (C57BL/6 background) received a standard or cholesterol-rich diet. Experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 10 and day 36.

Results

Although minimal differences in cartilage damage were found between the WT and ApoE^−/− mice, increased synovial thickening was found in the latter. Thirty-six days after OA-induction, ApoE^−/− mice on a standard diet showed increased ectopic bone formation, particularly at the medial collateral ligament, compared with OA in WT mice. Furthermore, a significant increase in synovial gene expression of both S100a8 and S100a9 and S100A8/S100A9 protein levels was found in ApoE^−/− mice, suggesting an activated inflammatory status of synovial cells.

In both ApoE^−/− and WT mice, addition of a cholesterol-rich diet resulted in excessive bone formation in the medial collateral ligament at late-time-point OA. Interestingly, at the early time point, proteoglycan deposition was already significantly increased in ApoE^−/− mice compared with WT mice. Mice deficient for both ApoE and S100a9 also showed increased ectopic bone formation, but not synovial activation, suggesting a role for S100-proteins in cholesterol-mediated synovial activation.

Conclusions

Increased cholesterol levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA.