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MEF2D as a key regulator of osteoarthritis with exploratory therapeutic potential
Jingjin Dai1, Xiaoshan Gong2, Hao Tang2
1Department of Biomedical Materials Science, Army Medical University, Chongqing, China; Frontier Medical Training Brigade, Army Medical University, Xinjiang, China.
Objective:
Osteoarthritis is the most common degenerative joint disease worldwide, characterized by degeneration of articular cartilage caused by chondrocyte dysfunction and invasion of vessels from subchondral bone. However, the molecular mechanisms governing the dyshomeostasis of cartilage and subchondral bone during osteoarthritis remain unclear. Emerging evidence indicates that myocyte enhancer factor 2D (MEF2D) promotes chondrocyte hypertrophy and vascularization, whereas its role in osteoarthritis has not yet been reported.
Methods:
To explore the role of MEF2D, we generated and identified MEF2D conditional knockout mice and established osteoarthritis models via DMM or ACLT surgery. Samples were evaluated using micro-CT, histological, and immunofluorescence analyses, whereas molecular mechanisms were elucidated by RNA-Seq, CUT&Tag, ChIP, and dual-luciferase reporter assays.
Results:
MEF2D was aberrantly overexpressed in murine osteoarthritis cartilage, whereas osteoarthritis progression was delayed in MEF2D knockout mice (p = 0.0359, OARSI grade, -1.048 [95% CI: -2.034, -0.06209]). Functionally, MEF2D bound to the promoter of lactate dehydrogenase A (LDHA) to activate its transcription, and induced the expression of inflammatory cytokines via LDHA/IκB-ζ signaling, which subsequently promoted the expression of catabolic genes. Moreover, MEF2D increased VEGF secretion by chondrocytes through upregulating brain-derived neurotrophic factor (BDNF) (p < 0.0001, MD = 9.486 [95% CI: 7.185, 9.622]). Additionally, BDNF secreted by chondrocytes binds to its receptor TrkB to form a BDNF/TrkB autocrine loop that positively regulates MEF2D expression (p = 0.0002, MD = 0.9250 [95% CI: 0.5709, 1.279]). Injection of a TrkB antagonist into the articular cavities of osteoarthritis model mice provided preliminary evidence of delayed cartilage degeneration, subchondral osteosclerosis, and osteophyte formation.
Conclusion:
Our study revealed a critical transcriptional regulatory role of MEF2D in osteoarthritis, and further suggested that targeting MEF2D may represent a potential therapeutic strategy.
