Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage(1). The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation(2-4). 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(5-7). 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. Endogenous skeletal stem cells are recruited to form cartilage in mice when stimulated by microfracture surgery together with localized delivery of growth factors, pointing to a new approach for treating cartilage defects.