气候变化领域集成服务门户(CCPortal): Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis

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DOI	10.1073/pnas.2001611118
	Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis
	Lee W.; Nims R.J.; Savadipour A.; Zhang Q.; Leddy H.A.; Liu F.; McNulty A.L.; Chen Y.; Guilak F.; Liedtke W.B.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies [A. M. Valdes, T. D. Spector, Nat. Rev. Rheumatol. 7, 23–32 (2011)]. We previously identified mechanosensitive PIEZO channels, PIEZO1 and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction in response to injury [W. Lee et al., Proc. Natl. Acad. Sci. U.S.A. 111, E5114–E5122 (2014); W. Lee, F. Guilak, W. Liedtke, Curr. Top. Membr. 79, 263–273 (2017)]. We therefore asked whether interleukin-1–mediated inflammatory signaling, as occurs in OA, influences Piezo gene expression and channel function, thus indicative of maladaptive reprogramming that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic cartilage tissue were studied. We found that interleukin-1α (IL-1α) up-regulated Piezo1 in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca2+ at baseline and in response to mechanical deformation. Elevated resting state Ca2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma. As intracellular substrates of this OA-related inflammatory pathomechanism, in porcine articular chondrocytes exposed to IL-1α, we discovered that enhanced Piezo1 expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1. CREBP1 directly bound to the proximal PIEZO1 gene promoter. Taken together, these signaling and genetic reprogramming events represent a detrimental Ca2+-driven feed-forward mechanism that can be rationally targeted to stem the progression of OA. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Interleukin-1; Osteoarthritis; PIEZO1; Piezo1 gene regulation
语种	英语
scopus关键词	activating transcription factor 2; calcium ion; F actin; hepatocyte nuclear factor 4; interleukin 1alpha; ion channel; messenger RNA; mitogen activated protein kinase p38; protein Piezo1; unclassified drug; actin filament; animal cell; Article; articular cartilage; calcium cell level; cell culture; chondrocyte; controlled study; disease exacerbation; female; human; human tissue; inflammation; mechanotransduction; nonhuman; osteoarthritis; pathogenesis; PIEZO1 gene; pig; positive feedback; priority journal; promoter region; protein expression; protein protein interaction; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180084
作者单位	Department of Neurology, Duke University, Durham, NC 27710, United States; Department of Biomedical Engineering, University of Rochester, Rochester, NY 14620, United States; Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14620, United States; Department of Orthopaedic Surgery, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, United States; Center of Regenerative Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, United States; Department of Orthopedics, Duke University, Durham, NC 27710, United States; Department of Neurobiology, Duke University, Durham, NC 27710, United States; Shriners Hospitals for Children–Saint Louis, St. Louis, MO 63110, United States; Department of Anesthesiology, Duke University, Durham, NC 27710, United States; Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders, Duke University School of Medicine, Durham, NC 27705, United States; Innovative Pain T...
推荐引用方式 GB/T 7714	Lee W.,Nims R.J.,Savadipour A.,et al. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis[J],2021,118(13).
APA	Lee W..,Nims R.J..,Savadipour A..,Zhang Q..,Leddy H.A..,...&Liedtke W.B..(2021).Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Lee W.,et al."Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).