Enhancement of DUSP14 (dual specificity phosphatase 14) limits osteoarthritis progression by alleviating chondrocyte injury, inflammation and metabolic homeostasis

ABSTRACT

Osteoarthritis (OA) is a proverbial inflammatory degenerative joint disease associated with the acceleration of the aging process and is characterized by chondrocyte injury and articular cartilage degradation. Dual-specificity phosphatase 14 (Dusp14), a common member of the DUSP family, has been implicated in multiple inflammatory diseases and bone loss. Nevertheless, the function of DUSP14 in OA remains unclear. In the present study, down-regulation of DUSP14 was corroborated in anterior cruciate ligament transection (ACLT)-induced OA rats and interleukin-1β (IL-1β)-stimulated chondrocytes. Additionally, the gain of DUSP14 reversed IL-1β-induced inhibition of chondrocyte viability but attenuated cell apoptosis. Concomitantly, DUSP14 overexpression muted IL-1β-induced release of pro-inflammatory mediators NO and prostaglandin E2 (PGE2), as well as pro-inflammatory cytokine levels (IL-6 and TNF-α). Furthermore, up-regulation of DUSP14 overturned the effects of IL-1β on the inhibition of collagen II and aggrecan expression, and enhancement of A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5) and matrix metalloproteinases (MMPs; MMP3 and MMP-13). Mechanistically, DUSP14 elevation increased the p-Adenosine 5ʹ-monophosphate-activated protein activated protein kinase(AMPK), inhibitor of NF-κB (IκB) expression and decreased p-p65 NF-κB expression, indicating that DUSP14 might restore the AMPK-IκB pathway to restrain NF-κB signaling under IL-1β exposure. Notably, blockage of AMPK signaling muted the protective efficacy of DUSP14 elevation against IL-1β-induced inflammatory injury and metabolism disturbance in chondrocytes. Interestingly, histological evaluation substantiated that DUSP14 injection alleviated cartilage degradation in OA rats. Together, DUSP14 may ameliorate OA progression by affecting chondrocyte injury, inflammatory response and cartilage metabolism homeostasis, implying a promising therapeutic strategy against OA.

KEYWORDS:

• Osteoarthritis
• chondrocyte
• inflammatory injury
• metabolism homeostasis
• dusp14

Significance of this study

Osteoarthritis (OA) is a common whole-point and debilitating disease worldwide and constitutes the major source of pain and disability among people. The current findings highlight that DUSP14 may ameliorate OA progression by affecting chondrocyte injury, inflammatory response and cartilage metabolism homeostasis. Therefore, this study may support DUSP14 as a promising therapeutic strategy against OA.

Authors’ contributions

ZDZ performed animal experiment, cell culture and qRT-PCR assay. JY carried out the animal experimental and western blotting analysis. LZ performed cell apoptosis and ELISA assay. YPZ designed the concept, and conducted animal experiments with ZDZ and JY together. All authors read and approved the final manuscript.

Disclosure statement

The authors declare there are no competing interests.

Availability of data and material

All data generated or analysed during this study are included in this published article.

Ethic approval

All animal experiments were performed according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals, and ethically approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University Health Science Center, Honghui Hospital (No. SYXK (Shan) 2020-006).

Highlights

★The expression of DUSP14 was decreased in OA model in vivo and in vitro

★DUSP14 alleviated IL-1β-evoked chondrocyte injury and inflammatory response

★DUSP14 affects metabolic homeostasis in IL-1β-stimulated chondrocytes

★The AMPK/IκB/NF-kB signaling mediates chondroprotective efficacy of DUSP14 elevation

★Elevation of DUSP14 ameliorates the progression of OA in vivo

Additional information

Funding

The authors declare no specific funding for this work.