Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis

Abstract

Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein–coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein–coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)–approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.

Resolvin D1‐loaded nanoliposomes promote M2 macrophage polarization and are effective in the treatment of osteoarthritis

“…Overall, we observed that the formulation was reducing the net inflammatory activity of the synovium by reducing M1 cells and promoting clearance of debris and other inflammatory factors by increasing M2 cells in the joint. Catabolic enzymes like ADAMTS5 and MMP13 are released by chondrocytes in OA and are considered as markers of chondrocyte hypertrophy 76 . Administration of Lipo‐RvD1 suppresses the expression of ADAMTS5 and MMP13, thus indicating the suppression of hypertrophic chondrocytes phenotype in OA in mice (Figure S10).…”

“…Catabolic enzymes like ADAMTS5 and MMP13 are released by chondrocytes in OA and are considered as markers of chondrocyte hypertrophy. 76 Administration of Lipo-RvD1 suppresses the expression of ADAMTS5 and MMP13, thus indicating the suppression of hypertrophic chondrocytes phenotype in OA in mice (Figure S10).…”

G Protein-Coupled Receptors in Osteoarthritis

“…Cartilage-specific GRK2 deletion promoted matrix regeneration and prevented OA progression. Furthermore, the GRK2-inhibiting antidepressant paroxetine decelerated OA progression in DMM mice (171). As a clinically used antidepressant with known pharmacological profiles and safety record, paroxetine offers a promising therapeutic strategy for OA that can be easily translated from bench side to clinics.…”

A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration

“…Cartilage anabolism is stimulated by cytokines and growth factors, including bone morphogenetic proteins (BMPs), transforming growth factor (TGF)-β and insulin-like growth factor I (IGF-I), which induce chondrogenesis related genes, such as Col2a1 , Acan , and Sox9 . These anabolic factors protect the cartilage integrity by enhancing proteoglycan and collagen synthesis, and thereby promoting a healthy extracellular matrix (ECM) structure 12 , 13 . The catabolic regulators, including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) promote degradation of the articular cartilage ECM through upregulation of matrix metalloproteinases (MMPs) and aggrecanases from the ADAMTS family of proteases 14 – 16 .…”