Abstract Osteoarthritis (OA) is a heterogeneous disease that is extremely hard to cure owing to its complex regulation network of pathogenesis, especially cartilage degeneration. FBXO21 is a subunit of ubiquitin E3 ligases that degrades P‐glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate‐induced OA rats, and chondrocytes treated with interleukin‐1β, tumor necrosis factor‐α, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA‐related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA‐related cartilage degeneration. In addition, using mass spectrometry and co‐immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB‐FBXO21‐ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA.

Zhiming Lin

Jianing Miao

Tao Zhang

Ming He

Ziyuan Wang

Xinyuan Feng

Lunhao Bai

Aging Cell

AGING CELL 的目标是发表最高质量的创新研究，解决衰老生物学的基本问题。为了在 AGING CELL 上发表，这项工作必须为理解老龄化提供重大的新贡献，并引起社区的普遍兴趣。 AGING CELL 力求涵盖老年科学的所有领域，突出揭示衰老过程的机制方面的研究，以及衰老与年龄相关疾病之间的联系。

Aging Cell aims to publish high-quality innovative research that addresses fundamental issues in the biology of aging. To be published in Aging Cell, the work must provide significant new contributions to the understanding of aging and garner broad interest within the community. Aging Cell seeks to cover all areas of geroscience, with a particular emphasis on research that reveals the mechanisms of the aging process and the connections between aging and age-related diseases.

《Aging Cell》旨在发表高质量的创新研究，解决衰老生物学中的基本问题。为了在《Aging Cell》上发表，研究必须为理解老龄化提供重要的新贡献，并引起学术界的广泛关注。《Aging Cell》力求涵盖老年科学的各个领域，特别强调揭示衰老过程机制的研究，以及衰老与年龄相关疾病之间的关系。

JUNB‐FBXO21‐ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy

It is revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate‐induced OA rats, and chondrocytes treated with interleukin‐1β, tumor necrosis factor‐α, and lipopolysaccharide and its knockdown may provide a novel targeted therapy for OA.

Category	Quartile
医学	1
医学, 老年医学	1
医学, 细胞生物学	2

JUNB‐FBXO21‐ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy

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Journal Info

Category	Quartile
GERIATRICS & GERONTOLOGY	1