Histone

Gene

Cell biology

Biology

Calcification

Apoptosis

Extracellular

Autophagy

Cartilage

Cancer research

Biochemistry

Environmental health

Alternative medicine

Anatomy

Osteoarthritis

Histone deacetylase

Population

Pathological

Medicine

Chemistry

HDAC6

Pathology

Science Advances

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.

Autophagic LC3 <sup>+</sup> calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

Autophagic LC3 + calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis