Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.
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2021-03
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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.
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Lee, Whasil, Robert J Nims, Alireza Savadipour, Qiaojuan Zhang, Holly A Leddy, Fang Liu, Amy L McNulty, Yong Chen, et al. (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). pp. e2001611118–e2001611118. 10.1073/pnas.2001611118 Retrieved from https://hdl.handle.net/10161/22727.
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Amy Lynn McNulty
The McNulty Lab is working to develop strategies to prevent osteoarthritis and to promote tissue repair and regeneration following joint injury. In order to accomplish this, we are working in three main areas. 1) We are working to understand the pathways that are activated by normal and injurious mechanical loading of cartilage and meniscus and how these mechanotransduction pathways are altered during aging, injury, and tissue degeneration. A greater understanding of alterations in mechanosensitive signaling mechanisms with aging and injury will likely reveal potential targets to promote tissue repair and prevent tissue degeneration and osteoarthritis development. 2) We are developing meniscus tissue engineered constructs that will be utilized to repair and replace meniscus tissue lost due to injury and surgical resection. 3) We are focusing on the biological and biomechanical changes that occur in the joint following meniscus injury and how these may contribute to osteoarthritis development.
Yong Chen
Dr. Yong Chen is an Associate Professor of Neurology at the Duke University School of Medicine. He is also affiliated with Duke Anesthesiology-Center for Translational Pain Medicine (CTPM) and Duke-Pathology.
The Chen lab mainly studies sensory neurobiology of pain and itch, with a focus on TRP ion channels and neural circuits. The main objective of our lab is to identify molecular and cellular mechanisms underlying chronic pain and chronic-disease associated itch, using a combination of animal behavioral, genetic, molecular and cellular, advanced imaging, viral, and optogenetic approaches. There are three major research areas in the lab: craniofacial pain, arthritis pain and joint function, and systemic-disease associated itch.
Wolfgang Bernhard Liedtke
Research Interests in the Liedtke-Lab:
- Pain/ nociception
- Sensory transduction and -transmission
- TRP ion channels
- Water and salt equilibrium regulated by the central nervous system
Visit the lab's website, download papers and read Dr. Liedtke's CV here.
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