Background:
Arthritis is a cartilage degenerative disease that is mainly induced by the degradation of the cartilage extracellular matrix (ECM), which is found to be regulated by the expression level of a
disintegrin and
metalloproteinase with
thrombospondin motifs 5 (ADAMT-5), an
enzyme degrading
Aggrecans in the ECM.
Feprazone is a classic nonsteroidal anti-inflammatory
drug with promising efficacy in
arthritis. The present study aims to investigate the protective effect of
Feprazone on the degraded
Aggrecan in the human chondrocytes induced with
tumor necrosis factor-α (TNF-α) and to clarify the underlying mechanism. Methods: To investigate the effect of
Feprazone, the CHON-001 chondrocytes were stimulated with TNF-α (10 ng/mL) in the presence or absence of
Feprazone (3, 6 μM) for 24 h. Mitochondrial membrane potential was evaluated using the
Rhodamine 123 assay. The gene expressions of interleukin-1β (IL-1β),
interleukin-8 (IL-8),
monocyte chemotactic protein 1 (MCP-1), and ADAMTS-5 in the treated chondrocytes were detected using real-time quantitative polymerase chain reaction (qRT-PCR), and the
protein levels of these targets were determined using
enzyme-linked
immunosorbent assay (ELISA). SOX-4 was knocked down by transfecting the
siRNA into the chondrocytes. Western blot analysis was utilized to evaluate the expression levels of SOX-4,
Aggrecan, and
protein kinase C (PKCα). Results: First, the reduced mitochondrial membrane potential (ΔΨm) and secretion of proinflammatory factors (IL-1β, IL-8, and MCP-1) induced by TNF-α were significantly reversed by treatment with
Feprazone. Second, the expression of
Aggrecan was significantly decreased by stimulation with TNF-α via upregulation of ADAMTS-5 but was dramatically reversed by the introduction of
Feprazone. Third, we found that TNF-α elevated the expression of ADAMTS-5 by upregulating SOX-4, which was observed to be related to the activation of PKCα. Lastly, the elevated expression of SOX-4 induced by TNF-α was significantly reversed by
Feprazone. Conclusions:
Feprazone might ameliorate TNF-α-induced loss of
Aggrecan via the inhibition of the SOX-4/ADAMTS-5 signaling pathway.