Insulin-like growth factor-1 regulates the mechanosensitivity of chondrocytes by modulating TRPV4. (November 2021)

• Record Type: Journal Article
• Authors: Trompeter, Nicholas; Gardinier, Joseph D.; DeBarros, Victor; Boggs, Mary; Gangadharan, Vimal; Cain, William J.; Hurd, Lauren; Duncan, Randall L.
• Is Part Of: Cell calcium. Volume 99(2021)
• Publication Date: 2021-11
• Subjects: Chondrocytes -- Mechanosensitivity -- IGF-1 -- TRPV4 -- Actin -- Hypotonic swelling; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2021.102467
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: IGF-1 suppresses hypotonic stimulation of the TRPV4 channel to reduce Ca 2+ influx in ATDC5 cells. IGF-1 stimulates the f-actin stress fiber formation which binds to the TRPV4 MAP7 binding domain to elicit this suppression. Mutation of the MAP7 site abrogates the response of cells to IGF-1. TRPV4 mediated [Ca 2+ ]i promotes ATP release from chondrocytes and is inhibited during IGF-1 treatment. Abstract: Both mechanical and biochemical stimulation are required for maintaining the integrity of articular cartilage. However, chondrocytes respond differently to mechanical stimuli in osteoarthritic cartilage when biochemical signaling pathways, such as Insulin-like Growth Factor-1 (IGF-1), are altered. The Transient Receptor Potential Vanilloid 4 (TRPV4) channel is central to chondrocyte mechanotransduction and regulation of cartilage homeostasis. Here, we propose that changes in IGF-1 can modulate TRPV4 channel activity. We demonstrate that physiologic levels of IGF-1 suppress hypotonic-induced TRPV4 currents and intracellular calcium flux by increasing apparent cell stiffness that correlates with actin stress fiber formation. Disruption of F-actin following IGF-1 treatment results in the return of the intracellular calcium response to hypotonic swelling. Using point mutations of the TRPV4 channel at the microtubule-associated protein 7 (MAP-7) site shows that regulation of TRPV4 by actin is mediated via the interaction of actin with the MAP-7 domain of TRPV4. We further highlight that ATP release, a down-stream response to mechanical stimulation in chondrocytes, is mediated by TRPV4 during hypotonic challenge. This response is significantly abrogated with IGF-1 treatment. As chondrocyte mechanosensitivity is greatly altered during osteoarthritis progression, IGF-1 presents as a promising candidate for prevention and treatment of articular cartilage damage. Graphical abstract: Image, graphical abstract