Year: 2021
Type: preprint
Abstract: During the progression of osteoarthritis (OA), degradation of the extracellular matrix alters the biomechanical properties of cartilage, especially the compressive modulus. The mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) is required for chondrocyte mechanotransduction However, how OA-mediated cartilage degradation influences TRPV4 signaling remains unknown. To determine if ATDC5 cells alter TRPV4-mediated calcium signaling and cell phenotype in response to softer substrates, we created PEGDA-RGDS hydrogels with Young’s moduli that simulated healthy (~350 kPa), OA (~175 kPa) and severe OA (~35 kPa) tissue. We found that softer substrates reduced the influx of calcium through TRPV4 when challenging chondrocytes with hypotonic swelling (HTS). Chondrocyte apoptosis also increased on the OA and severe OA gels due to elevated basal [Ca 2+ ] i , which is attenuated with pharmacological agonism of TRPV4. Pharmacological agonism of TRPV4 rescued the expression of aggrecan and TRPV4 in chondrocytes cultured on OA gels and enhanced the type II collagen (col2) expression in cells on the normal and OA gels. These data suggest that the biomechanical properties of degraded cartilage alter TRPV4-mediated mechanotransduction in chondrocytes. Given that TRPV4 reduced apoptosis and improved the chondrogenic capacity of cells, TRPV4 stimulation could provide a potential therapeutic target in patients with early to moderate OA.
Institutions: University of Delaware, University of Michigan–Flint
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1705962760, G3115553707, A Vascularized, In Vitro, Organotropic Metastasis Model to Generate Dormant Micrometastases, Delaware EPSCoR: Meeting Delaware's 21st Century Water and Energy Challenges through Research, Education, and Innovation, CAREER: Development of a Tissue-Engineered Model of Ischemic Microstroke, G7473849405, Pressure in lung development and congenital diaphragmatic hernia, G9000125231, Delaware INBRE, Delaware Clinical and Translational Research ACCEL Program
OpenAlex ID: W3199747167