Pathological cartilage calcification plays an important role in osteoarthritis progression but in which the origin of calcified extracellular vesicles (EVs) and their effects remain unknown. Here, we demonstrate that pathological cartilage calcification occurs in the early stage of the osteoarthritis in which the calcified EVs are closely involved. Autophagosomes carrying the minerals are released in EVs, and calcification is induced by those autophagy-regulated calcified EVs. Autophagy-derived microtubule-associated proteins 1A/1B light chain 3B (LC3)–positive EVs are the major population of calcified EVs that initiate pathological calcification. Release of LC3-positive calcified EVs is caused by blockage of the autophagy flux resulted from histone deacetylase 6 (HDAC6)–mediated microtubule destabilization. Inhibition of HDAC6 activity blocks the release of the LC3-positive calcified EVs by chondrocytes and effectively reverses the pathological calcification and degradation of cartilage. The present work discovers that calcified EVs derived from autophagosomes initiate pathological cartilage calcification in osteoarthritis, with potential therapeutic targeting implication.
Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the β2-adrenergic receptor (β2AR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
Objectives
The treatment of bone defects by stem cells (MSCs) has achieved limited success over the recent few decades. The emergence of exosomes provides a new strategy for bone regeneration. Here, we aimed to investigate the effect and mechanisms of exosomes combined with dental pulp stem cells (DPSCs) on bone regeneration.
Materials and Methods
We isolated exosomes from stem cells from human exfoliated deciduous teeth (SHED) aggregates and evaluated the efficacy of exosomes combined with DPSCs in a cranial bone defect model. The potential mechanisms were further investigated.
Results
The effect of exosomes combined with DPSCs was remarkable on bone regeneration in vivo and exosomes promoted osteogenic differentiation of DPSCs in vitro. Mechanistically, exosomes increased the expression of mitochondrial transcription factor A (TFAM) in DPSCs by transferring TFAM mRNA. Moreover, highly expressed TFAM in DPSCs enhanced glutamate metabolism and oxidative phosphorylation (OXPHOS) activity.
Conclusions
Consequently, exosomes strengthened bone regeneration of DPSCs through the activation of mitochondrial aerobic metabolism. Our study provides a new potential strategy to improve DPSC‐based bone regenerative treatment.
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