Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis

Abstract

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.

Integrins, cadherins and channels in cartilage mechanotransduction: perspectives for future regeneration strategies

“…At the transcriptional level, increased PIEZO1 expression was governed by MAP-kinase p38 and transcription factors including cellular retinol binding protein 1 (CREBP1), activating transcription factor 2 (ATF2) or hepatocyte nuclear factor 4 (HNF4) (Ref. 96). In addition to the above-mentioned channels, which regulate intracellular calcium levels, VGCCs such as L-type alpha 1C subunit (Cav1.2) have recently been shown to be indispensable for chondrogenesis during limb development in chicken or mouse embryos.…”

Effect of knee joint loading on chondrocyte mechano-vulnerability and severity of post-traumatic osteoarthritis induced by ACL-injury in mice

“…A group of mechanosensing and mechanotransducing molecules may be regulated over PT-OA development and tune cellular mechano-sensitivity under abnormal joint mechanics and inflammation post-ACL-I. For instance, dysregulated integrin αVβ3 and their associated ligands may play essential roles in disrupting chondrocyte-ECM interactions over OA progression [77][78][79] , as well as Piezo1 may be augmented via IL-1-mediated inflammatory patho-mechanisms 80,81 . Future research will investigate the chondrocyte mechano-vulnerability based on mechanosensors and mechanotransducers and their local ECM properties over PT-OA development.…”

Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone

“…Interleukin-1α (IL-1α) was found to upregulate Piezo1 in porcine chondrocytes in vitro, which resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess Ca 2+ influx in response to mechanical deformation [ 112 ]. Elevated resting state Ca 2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma [ 112 ]. Increased Piezo1 expression depends on transcription factor CREBP1 which directly binds to the proximal Piezo1 gene promoter [ 112 ].…”

“…Elevated resting state Ca 2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma [ 112 ]. Increased Piezo1 expression depends on transcription factor CREBP1 which directly binds to the proximal Piezo1 gene promoter [ 112 ]. Thus, targeted inhibition of IL-1α- CREBP1-Piezo1 can inhibit the development of OA.…”