Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice

Wu, Xiaohao1,8; Chen, Mingjue1; Lin, Sixiong2; Chen, Sheng3; Gu, Jingliang4; Wu, Yuchen5; Qu, Minghao1; Gong, Weiyuan1; Yao, Qing1; Li, Huiping6; Zou, Xuenong2; Chen, Di7; Xiao, Guozhi1,8

2023-02-01

10.14336/AD.2023.0212

Aging and Disease   Impact Factor & Quartile

2152-5250

Degenerative disc disease (DDD) is one of the most common skeletal disorders affecting aged populations. DDD is the leading cause of low back/neck pain, resulting in disability and huge socioeconomic burdens. However, the molecular mechanisms underlying DDD initiation and progression remain poorly understood. Pinch1 and Pinch2 are LIM-domain-containing proteins with crucial functions in mediating multiple fundamental biological processes, such as focal adhesion, cytoskeletal organization, cell proliferation, migration, and survival. In this study, we found that Pinch1 and Pinch2 were both highly expressed in healthy intervertebral discs (IVDs) and dramatically downregulated in degenerative IVDs in mice. Deleting Pinch1 in aggrecanexpressing cells and Pinch2 globally (AggrecanCreERT2; Pinch1fl/fl; Pinch2-/-) caused striking spontaneous DDD-like lesions in lumbar IVDs in mice. Pinch loss inhibited cell proliferation and promotes extracellular matrix (ECM) degradation and apoptosis in lumbar IVDs. Pinch loss markedly enhanced the production of pro-inflammatory cytokines, especially TNF alpha, in lumbar IVDs and exacerbated instability-induced DDD defects in mice. Pharmacological inhibition of TNF alpha signaling mitigated the DDD-like lesions caused by Pinch loss. In human degenerative NP samples, reduced expression of Pinch proteins was correlated with severe DDD progression and a markedly upregulated expression of TNF alpha. Collectively, we demonstrate the crucial role of Pinch proteins in maintaining IVD homeostasis and define a potential therapeutic target for DDD.

Pinch disc degeneration inflammation anti-TNF? therapy Adalimumab

SCI

English

First ; Corresponding

National Key Research and Development Program of China[2019YFA0906004] ; National Natural Science Foundation of China["82230081","82250710175","82172375","81991513","82261160395"] ; Shenzhen Stable Support Plan Program for Higher Education Institutions[20200925150409001] ; Shenzhen Fundamental Research Program[JCYJ20220 818100617036] ; Shenzhen Key Laboratory of Cell Microenvironment Grant[ZDSYS20140509142721429] ; Guangdong Provincial Science and Technology Innovation Council[2017B030301018]

Geriatrics & Gerontology

Geriatrics & Gerontology

WOS:000937440200001

INT SOC AGING & DISEASE

Web of Science

1.Southern Univ Sci & Technol, Dept Biochem, Shenzhen Key Lab Cell Microenvironm, Sch Med,Guangdong Prov Key Lab Cell Microenvironm, Shenzhen, Peoples R China
2.Sun Yat Sen Univ, Affiliated Hosp 1, Dept Spine Surg, Guangdong Prov Key Lab Orthopaed & Traumatol, Guangzhou, Peoples R China
3.Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Orthoped, Wuhan 430022, Hubei, Peoples R China
4.Shanghai Univ Tradit Chinese Med, Shanghai municipal Hosp Tradit Chinese Med, Dept Orthoped, Shanghai, Peoples R China
5.Chongqing Tradit Chinese Med Hosp, Dept Endocrinol, Chongqing, Peoples R China
6.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Dept Resp & Crit Care Med, Shenzhen, Peoples R China
7.Chinese Acad Sci, Shenzhen Inst Adv Technol, Res Ctr Human Tissues & Organs Degenerat, Shenzhen, Peoples R China
8.Southern Univ Sci & Technol, Sch Med, Shenzhen Key Lab Cell Microenvironm, Shenzhen, Peoples R China

Wu, Xiaohao,Chen, Mingjue,Lin, Sixiong,et al. Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice[J]. Aging and Disease,2023.

Wu, Xiaohao.,Chen, Mingjue.,Lin, Sixiong.,Chen, Sheng.,Gu, Jingliang.,...&Xiao, Guozhi.(2023).Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice.Aging and Disease.

Wu, Xiaohao,et al."Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice".Aging and Disease (2023).