Bone remodeling stimulated by Wnt-mediated mitophagy regulated extracellular vesicles in subchondral bone contributes to osteoarthritis development

Oct 3, 2025Theranostics

Bone remodeling triggered by cell-cleaning signals from subchondral bone supports osteoarthritis development

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Extracellular vesicles (EVs) from different osteoblast subtypes exhibit distinct effects on subchondral bone remodeling and osteoarthritis progression.

EVs from mineralizing osteoblasts (MinOBs) significantly enhanced osteogenic differentiation and mineralization.
MinOB-derived EVs contained specific pro-osteogenic miRNAs and increased calcium phosphate content.
Distinct pro-angiogenic and cartilage-degrading effects were observed across different osteoblast subtype-derived EVs.
Wnt signaling was found to dynamically regulate mitophagy and the composition of EVs, particularly in MinOBs.
In vivo, administration of osteoblast-derived EVs led to exacerbated subchondral bone sclerosis and cartilage degradation, with MinOB-EVs causing the most severe changes.

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Osteoarthritis (OA) is increasingly understood as a disease involving not only cartilage degeneration but also pathological subchondral bone remodeling. The contribution of osteoblast (OB) heterogeneity and their secreted extracellular vesicles (EVs) to this process remains poorly characterized. This study aims to investigate how EVs from distinct OB subtypes modulate subchondral bone remodeling and contribute to OA progression.OB subtypes representing endothelial (EnOBs), stromal (StOBs), and mineralizing (MinOBs) stages were generated by time-controlled osteogenic induction of BMSCs. EVs were isolated from each OB subtype and characterized by TEM, Western blot, DLS, and miRNA profiling. Functional assays included osteogenic induction, angiogenesis, and cartilage degradation analyses in vitro. RNA-seq and qRT-PCR were used to identify relevant signaling pathways and miRNAs. In vivo effects of EVs were tested in a DMM-induced OA mouse model using intravenous injections, followed by histology, micro-CT, and immunostaining.EVs derived from different OB subtypes exhibited distinct pro-osteogenic, pro-angiogenic, and cartilage-degrading effects. MinOB-derived EVs significantly enhanced osteogenic differentiation and mineralization, correlated with enrichment of calcium phosphate content and specific pro-osteogenic miRNAs. These EVs also carried amorphous calcium phosphate and mitochondrial content, linked to activated mitophagy. Wnt signaling dynamically regulated mitophagy and EV composition, particularly in MinOBs. In vivo, tail vein administration of OB-derived EVs exacerbated subchondral bone sclerosis and cartilage degradation in a time-dependent manner, with MinOB-EVs inducing the most pronounced pathological changes.OB-derived EVs exhibit subtype-dependent regulatory functions in subchondral bone remodeling, mediated by distinct miRNA profiles and mineral cargo shaped by Wnt-regulated mitophagy. These EVs actively participate in OA progression, and their effects vary with disease stage and route of administration. Targeting specific OB subtypes or modulating Wnt-mitophagy signaling may offer novel therapeutic strategies for stage-specific OA intervention. Rationale: Methods: Results: Conclusions:

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Bone remodeling stimulated by Wnt-mediated mitophagy regulated extracellular vesicles in subchondral bone contributes to osteoarthritis development

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