ELAVL1 promotes ferroptosis via the TRIM21/HOXD8 axis to inhibit osteogenic differentiation in congenital pseudoarticular tibia‐derived mesenchymal stem cells

TL;DR

This study shows how ELAVL1 promotes cell death in stem cells, which hinders bone development in a rare bone condition.

Contribution

The novel finding is that ELAVL1 promotes ferroptosis via TRIM21/HOXD8 interactions to inhibit osteogenic differentiation in CPT MSCs.

Findings

ELAVL1 and TRIM21 are upregulated, while HOXD8 is downregulated in CPT MSCs.

ELAVL1 promotes ferroptosis by stabilizing TRIM21, which ubiquitinates and degrades HOXD8.

Knockdown of ELAVL1 or TRIM21 inhibits ferroptosis and promotes osteogenic differentiation.

Abstract

Osteogenic differentiation of mesenchymal stem cells (MSCs) was strongly correlated with the progression of congenital tibial pseudoarthrosis (CPT). Activation of ferroptosis inhibited osteogenic differentiation of MSCs. ELAV‐like RNA binding protein 1 (ELAVL1) is a key factor in promoting ferroptosis. This study aimed to elucidate the mechanism of ELAVL1 in the osteogenic differentiation of CPT periosteum‐derived MSCs. Osteogenic differentiation of CPT periosteum‐derived MSCs was detected by ARS and ALP staining. Fe2+ content and lipid reactive oxygen species content were measured using commercial kits. Molecular interactions were verified using RIP, RNA pulldown, and Co‐IP. The ubiquitination level of homeobox gene D8 (HOXD8) was detected using Co‐IP. Expression of ELAVL1 and tripartite motif containing 21 (TRIM21) was upregulated in CPT periosteum‐derived MSCs, whereas HOXD8 expression was downregulated. Moreover, knockdown of ELAVL1 or TRIM21 inhibited ferroptosis and promoted osteogenic differentiation of CPT MSCs. TRIM21 overexpression reversed the effect caused by knockdown of ELAVL1. Mechanistically, ELAVL1 upregulated TRIM21 by increasing the stability of TRIM21, which ubiquitinated and degraded HOXD8. ELAVL1 bound to TRIM21, which promoted ubiquitination and degradation of HOXD8, thereby promoting ferroptosis to inhibit osteogenic differentiation of CPT MSCs.

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