Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage¹. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation^2,3,4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis^5,6,7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.

骨关节炎 (OA) 是一种退行性疾病，会导致关节软骨不可逆、进行性破坏¹。OA 的病因复杂，涉及多种因素，包括遗传易感性、急性损伤和慢性炎症^2,3,4。在这里，我们研究常驻骨骼干细胞 (SSC) 群体再生软骨的能力与年龄的关系，这可能是骨关节炎发展的一个因素^5,6,7. 我们证明衰老与 SSC 的逐渐丧失和小鼠和人类关节的软骨形成减少有关。然而，通过使用微骨折 (MF) 手术刺激再生反应，仍然可以在小鼠成年肢体关节的软骨表面触发 SSC 的局部扩张。尽管 MF 激活的 SSC 倾向于形成纤维组织，但 BMP2 和可溶性 VEGFR1 (sVEGFR1)（一种 VEGF 受体拮抗剂）在水凝胶中的局部共递送会偏向 MF 激活的 SSC 向关节软骨的分化。这些数据表明，在 MF 之后，可以诱导常驻干细胞群产生软骨，用于治疗 OA 中的局部软骨疾病。