Inhibition of syndecan-4 reduces cartilage degradation in murine models of osteoarthritis through the downregulation of HIF-2 alpha by miR-96-5p

作者全名："Zhou, Kai; He, Sirong; Yu, Haoda; Pei, Fuxing; Zhou, Zongke"

作者地址："[Zhou, Kai; Yu, Haoda; Pei, Fuxing; Zhou, Zongke] Sichuan Univ, West China Hosp, Dept Orthoped, Chengdu, Peoples R China; [He, Sirong] Chongqing Med Univ, Dept Immunol, Chongqing, Peoples R China"

通信作者："Zhou, K (corresponding author), Sichuan Univ, West China Hosp, Dept Orthoped, Chengdu, Peoples R China."

来源：LABORATORY INVESTIGATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000639722500001

JCR分区：Q1

影响因子：5

年份：2021

卷号：101

期号：8

开始页：1060

结束页：1070

文献类型：Article

关键词：　

摘要："The m6A modification level of LncRNA FENDRR is elevated in endometrioid endometrial carcinoma (EEC) cells and the abundant m6A modification promotes FENDRR degradation via recruiting the m6A binding protein YTHDF2. Subsequently, the downregulation of FENDRR resulted in the accumulation of SOX4 protein, thus boosting the proliferation of EEC cells. The membranous receptor syndecan-4 (SDC-4) and the nuclear transcription factor hypoxia-induced factor-2 alpha (HIF-2 alpha) play critical roles in the pathogenesis of osteoarthritis (OA). The aim of this study was to determine whether SDC-4 inhibition downregulates HIF-2a expression by microRNA-96-5p (miR-96-5p) in murine chondrocyte and cartilage tissue. The OA model was induced surgically in mice, and SDC-4 polyclonal antibody, HIF-2 alpha small interfering RNA (siRNA) and its control, miR-96-5p mimics and its scrambled controls or anti-miR-96-5p and its control were then injected into the knee joints. At 2 and 4 weeks after surgery, OA progression was evaluated microscopically, histologically, radiographically and immunohistochemically in these mice. Real-time polymerase chain reaction (RT-PCR) and western blotting were performed after treating with antibody and transfecting with miRNA mimic or siRNA to determine their effects on OA-related mediators. The potential miRNAs related to OA development were identified by using miRNA microarray analysis. Whether miRNAs play a pivotal role in OA development in vivo or in vitro was also investigated. MiR-96-5p expression was upregulated by SDC-4-specific antibodies in chondrocytes and cartilage tissue, and miR-96-5p directly targeted the 3 '-UTR of HIF-2 alpha to inhibit HIF-2 alpha signaling in murine chondrocytes. Moreover, we demonstrated that anti-SDC-4-attenuated IL-1 beta-induced chondrocyte hypertrophy and cartilage degradation by inhibiting HIF-2 alpha signaling by a miR-96-5p-dependent mechanism. Our study revealed that the inhibition of SDC-4 exerts its effects on both cartilage homeostasis and the chondrocyte hypertrophy phenotype by inducing miR-96-5p expression, which results in targeting HIF-2 alpha 3 '-UTR sequences and inhibiting HIF-2 alpha in murine cartilage tissue and chondrocytes."

基金机构："Sichuan Science and Technology Department Key Research Projects [2019YFS0129]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2019M653419]; West China Hospital, Sichuan UniversitySichuan University [2018HXBH049]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [82002304]"

基金资助正文："The study was supported by the Sichuan Science and Technology Department Key Research Projects (No. 2019YFS0129), the China Postdoctoral Science Foundation (No. 2019M653419), the Post-Doctor Research Project, West China Hospital, Sichuan University (No. 2018HXBH049), and the National Natural Science Foundation of China (No. 82002304). The funding source had no role in the study design; the acquisition, analysis, or interpretation of the data; the writing of the paper; or the decision to submit the paper for publication."