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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2024 Vol.25 No.6 P.513-528
Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis
Abstract: Osteoarthritis (OA) is a chronic progressive osteoarthropathy in the elderly. Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA. However, the specific mechanism of osteoclast differentiation in OA remains unclear. In our study, gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus (GEO) repository. GEO2R and Funrich analysis tools were employed to find differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that chemical carcinogenesis, reactive oxygen species (ROS), and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone. Furthermore, fourteen DEGs that are associated with oxidative stress were identified. The first ranked differential gene, heme oxygenase 1 (HMOX1), was selected for further validation. Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of HMOX1. Carnosol was revealed to inhibit osteoclastogenesis by targeting HMOX1 and upregulating the expression of antioxidant protein in vitro. Meanwhile, carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo. Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA. Targeting HMOX1 in subchondral osteoclasts may offer novel insights for the treatment of early OA.
Key words: Osteoclast; Oxidative stress; Osteoarthritis (OA); Heme oxygenase 1 (HMOX1); Carnosol
Chinese Summary <3> 血红素加氧酶1与骨关节炎软骨下破骨细胞失活的相关研究
1苏州大学第一附属医院骨科，中国苏州市，215006
2宜兴市人民医院骨科，中国宜兴市，214299
3海安人民医院骨科，中国海安市，226600
4上海交通大学医学院附属苏州九龙医院骨科，中国苏州市，215028
摘要：骨关节炎（OA）是一种老年慢性进行性骨关节病。破骨细胞活化在早期骨关节炎软骨下骨丢失的发生中起着至关重要的作用。然而，骨性关节炎中破骨细胞分化的具体机制尚不清楚。在本研究中，从基因表达综合库（GEO）中筛选了与OA疾病进展和破骨细胞活化相关的基因表达谱。采用GEO2R和Funrich分析工具寻找差异表达基因（DEGs）。富集分析结果表明，化学致癌作用、活性氧和氧化应激反应主要参与OA软骨下骨的破骨细胞分化。此外，还鉴定了14个与氧化应激相关的DEGs。选择排名第一的差异基因血红素加氧酶1（HMOX1）进行进一步验证。相关结果显示，OA软骨下骨破骨细胞活化过程中伴随着HMOX1的下调。在体外实验中发现，鼠尾草酚通过靶向HMOX1，上调抗氧化蛋白的表达来抑制破骨细胞的形成。同时，在体内发现鼠尾草酚通过抑制软骨下骨破骨细胞的激活来减轻OA的严重程度。综上所述，软骨下骨氧化还原失稳态引起的破骨细胞活化是骨性关节炎进展的重要途径。在软骨下破骨细胞中靶向HMOX1可为早期OA的治疗提供新的见解。
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DOI:
10.1631/jzus.B2300303
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On-line Access:
2024-06-24
Received:
2023-05-08
Revision Accepted:
2023-08-09
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2024-06-24
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