Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.
Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.
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DOI：
10.1136/annrheumdis-2015-208268
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发表时间：
2016-11
影响因子：
27.4
通讯作者：
Ferrell WR
中科院分区：
文献类型：
--
作者：
Huesa C;Ortiz AC;Dunning L;McGavin L;Bennett L;McIntosh K;Crilly A;Kurowska-Stolarska M;Plevin R;van 't Hof RJ;Rowan AD;McInnes IB;Goodyear CS;Lockhart JC;Ferrell WR
蛋白酶激活受体 2 (PAR2) 缺陷可防止实验性骨关节炎 (OA) 中的软骨退化。该途径对 OA 相关病理（例如骨赘形成和疼痛）的更广泛影响尚不清楚。在此，我们研究了实验性 OA 中早期颞骨和软骨的变化，以进一步阐明 PAR2 在 OA 发病机制中的作用。通过破坏内侧半月板 (DMM) 的稳定性，在野生型 (WT) 和 PAR2 缺陷型 (PAR2−/−) 小鼠中诱导 OA。使用组织学和 microCT 监测炎症、软骨退化和骨骼变化。在基因拯救实验中，PAR2−/− 小鼠关节内注射了表达人 PAR2 (hPAR2) 的腺病毒。动态负重被用作骨关节炎相关疼痛的替代指标。 WT 小鼠 DMM 后 7 天内形成骨赘，但诱导后 14 天内骨硬化才明显。重要的是，PAR2 在骨赘内的增殖/肥大软骨细胞中表达。在 PAR2−/− 小鼠中，骨赘形成的频率明显较低，但即使存在，骨赘也较小且密度较大；直到第 28 天，这些小鼠中都没有观察到骨硬化。PAR2−/− 小鼠的负重模式发生了改变，表明疼痛感知减少。 PAR2−/− 小鼠中 hPAR2 的表达再现了与 WT 小鼠中观察到的类似的骨赘形成和软骨损伤。然而，骨硬化不存在，这与软骨下骨中缺乏 hPAR2 表达一致。这项研究清楚地表明，PAR2 通过软骨细胞在骨赘发育和软骨下骨变化中发挥关键作用，这些变化发生在 PAR2 介导的软骨损伤之前。后者的发生可能与 OA 相关的骨骼变化无关。
Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis. OA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain. Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone. This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.
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影响因子：
2.8
作者：
O'Neill, Kevin R.;Stutz, Christopher M.;Schoenecker, Jonathan G.
通讯作者：
Schoenecker, Jonathan G.
影响因子：
13.3
作者：
Jackson, Miriam T.;Moradi, Babak;Little, Christopher B.
通讯作者：
Little, Christopher B.
影响因子：
--
作者：
Milner, Jennifer M.;Patel, Amit;Rowan, Andrew D.
通讯作者：
Rowan, Andrew D.
影响因子：
7
作者：
Glasson, S. S.;Blanchet, T. J.;Morris, E. A.
通讯作者：
Morris, E. A.
影响因子：
4
作者：
Tindell, Alistair G.;Kelso, Elizabeth B.;McInnes, Iain B.
通讯作者：
McInnes, Iain B.