Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice
Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice
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DOI：
10.1073/pnas.1514854113
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发表时间：
2016-05-10
影响因子：
11.1
通讯作者：
Hay, Eric
中科院分区：
文献类型：
--
作者：
Bouaziz, Wafa;Sigaux, Johanna;Hay, Eric
低氧压(低氧)调节软骨细胞的分化和代谢。低氧诱导因子1α(HIF1α)是软骨细胞发育过程中生长和存活的重要低氧因子。主要金属蛋白酶基质金属蛋白酶13(MMP13)也与成人关节软骨细胞肥大有关，在小鼠关节软骨中，MMP13的缺失对软骨退化和骨关节炎(OA)具有保护作用。MMP13受Wnt/β-catenin信号通路上调，Wnt/β-catenin信号通路参与软骨细胞分解代谢和骨关节炎。我们研究了HIF1α在软骨和骨关节炎中调节Wnt信号的作用。我们使用了有条件地敲除HIF1α(Delta HIF1α(CHON))的小鼠，并伴有关节不稳定。HIF1α的特异性缺失加剧了MMP13的表达和软骨破坏。缺氧软骨细胞Wnt信号分析显示，HIF1α可降低转录因子4(TCF4)-β-连环蛋白转录活性，抑制MMP13的表达。事实上，HIF1α与α-连环蛋白相互作用取代了MMP13调控序列中的TCF4。最后，Delta HIF1α(CHON)小鼠关节内注射PKF118-310(一种TCF4-α-catenin相互作用的抑制剂)后，软骨降解较少，软骨MMP13表达减少。因此，HIF1α-α-catenin相互作用是Wnt信号和MMP13转录的负调节因子，从而减少了骨关节炎的分解代谢。我们的研究有助于理解HIF1α在骨性关节炎中的作用，并强调了HIF1α-α-连环蛋白的相互作用，从而为研究低氧对关节软骨的影响提供了新的见解。
Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1 alpha (HIF1 alpha) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice. MMP13 is up-regulated by the Wnt/beta-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1 alpha in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of HIF1 alpha (Delta Hif1 alpha(chon)) with joint instability. Specific loss of HIF1 alpha exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1 alpha lowered transcription factor 4 (TCF4)-beta-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1 alpha interacting with alpha-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, Delta HIF1 alpha(chon) mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-alpha-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1 alpha-alpha-catenin interaction is a negative regulator of Wnt signaling and MMP13 transcription, thus reducing catabolism in OA. Our study contributes to the understanding of the role of HIF1 alpha in OA and highlights the HIF1 alpha-alpha-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.