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Fig. 8 | Biology Direct

Fig. 8

From: Prmt1-mediated methylation regulates Ncoa4 stability to transactivate Adamts genes and promote bone extracellular matrix degradation in chronic hematogenous osteomyelitis

Fig. 8

Schematic models of the Prmt1/Ncoa4-Cbp-Ap1/Adamts signaling axis in CHOM pathogenesis and its therapeutic inhibition. (A) Mechanism of Prmt1/Ncoa4-Cbp-Ap1/Adamts axis in CHOM pathogenesis. Upon S. aureus infection, proinflammatory cytokines upregulate Prmt1 expression in osteoblasts and osteocytes. Prmt1 catalyzes the methylation of Ncoa4, enhancing its stability. Methylated Ncoa4 forms a transcriptional complex with Cbp and Ap1 subunits, which binds to the promoters of Adamts3/8/12/14, driving their transcriptional activation. The upregulation of Adamts proteins promotes bone ECM degradation, leading to bone destruction and the development of CHOM. (B) Therapeutic inhibition of Prmt1 to prevent CHOM progression. Treatment with Prmt1 inhibitors (TCE-5003 and MS023) suppresses Ncoa4 methylation. Unmethylated Ncoa4 is ubiquitinated by the E3 ligase Rnf8 and subsequently degraded via the proteasome pathway. This degradation disrupts the Ncoa4-Cbp-Ap1 transcriptional complex, leading to the downregulation of Adamts3/8/12/14 expression. Consequently, bone ECM degradation is attenuated, preventing bone destruction and halting CHOM progression

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Biology Direct

ISSN: 1745-6150

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