Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis

Miao CHU; Guangdong CHEN; Kai CHEN; Pengfei ZHU; Zhen WANG; Zhonglai QIAN; Huaqiang TAO; Yaozeng XU; Dechun GENG

doi:10.1631/jzus.B2300303

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Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis

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Research Article | Updated：2024-06-24

Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis
Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis
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
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 25, Issue 6, Pages: 513-528(2024)
Affiliations：

1.Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
2.Department of Orthopedics, Yixing People’s Hospital, Yixing 214200, China
3.Department of Orthopedics, Hai’an People’s Hospital, Hai’an 226600, China
4.Department of Orthopedics, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 215028, China
Funds：
DOI：10.1631/jzus.B2300303
CLC：
CSTR：
Published： 15 June 2024 ，

Received： 08 May 2023 ，

Revised： 09 August 2023 ，

储淼,陈广东,陈楷等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(06):513-528.

Miao CHU, Guangdong CHEN, Kai CHEN, et al. Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(6):513-528(2024)
储淼,陈广东,陈楷等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(06):513-528. DOI： 10.1631/jzus.B2300303.

Miao CHU, Guangdong CHEN, Kai CHEN, et al. Heme oxygenase 1 linked to inactivation of subchondral osteoclasts in osteoarthritis. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(6):513-528(2024) DOI： 10.1631/jzus.B2300303.

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。

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 carci

nogenesis

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.

关键词

破骨细胞氧化应激骨关节炎（OA）血红素加氧酶1（HMOX1）鼠尾草酚

Keywords

OsteoclastOxidative stressOsteoarthritis (OA)Heme oxygenase 1 (HMOX1)Carnosol

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