Research ArticleRegenerative Medicine

Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis

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Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eaax9086
DOI: 10.1126/scitranslmed.aax9086

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Augmenting joint regeneration with agrin

Injured cartilage can be difficultly repaired and contributes to osteoarthritis progression. Eldridge et al. studied the osteochondral regenerative properties of the proteoglycan agrin. Injecting agrin into the joints of mice with osteochondral defects recruited progenitor cells to the injury site, promoted their differentiation into chondrocytes, and restored the bone-cartilage interface. Similar effects were seen in sheep treated with agrin-collagen gel, suggesting that agrin may have therapeutic utility for promoting osteochondral regeneration.

Abstract

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signaling downstream of β-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.

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