Abstract
Osteoarthritis (OA) is a common joint disease that results from the disintegration of joint cartilage and the underlying bone. Because cartilage and chondrocytes lack the ability to self-regenerate, efforts have been made to utilize stem cells to treat OA. Although various methods have been used to differentiate stem cells into functional chondrocytes, the currently available methods cannot induce stem cells to undergo differentiation into chondrocyte-like cells without inducing characteristics of hypertrophic chondrocytes, which finally lead to cartilage disintegration and calcification. Therefore, an optimized method to differentiate stem cells into chondrocytes that do not display undesired phenotypes is needed. This study focused on differentiating adipose-derived stem cells (ASCs) into functional chondrocytes using a small molecule that regulated the expression of Sox9 as a key factor in cartilage development and then explored its ability to treat OA. We selected ellipticine (ELPC), which induces chondrocyte differentiation of ASCs, using a GFP-Sox9 promoter vector screening system. An in vivo study was performed to confirm the recovery rate of cartilage regeneration with ASC differentiation into chondrocytes by ELPC in a collagenase-induced animal model of OA. Taken together, these data indicate that ellipticine induces ASCs to differentiate into mature chondrocytes without hypertrophic chondrocytes in vitro and in vivo, thus overcoming a problem encountered in previous studies. These results indicate that ELPC is a novel chondrocyte differentiation-inducing drug that shows potential as a cell therapy for OA.
Highlights
Osteoarthritis (OA) is a major degenerative and common chronic joint disease caused mainly by aging[1,2]
The articular cartilage composed of chondrocytes and a dense extracellular matrix (ECM) is a key component of joints that have a limited capacity for intrinsic healing and repair[6,7]
Screening of small molecules that induce the differentiation of adipose-derived stem cells (ASCs) into chondrocytes First, we found that the mRNA and protein levels of the sex-determining region Y-type high mobility group box (Sox)[9] were higher in chondrocytes than in ASCs (Fig. 1a, b)
Summary
Osteoarthritis (OA) is a major degenerative and common chronic joint disease caused mainly by aging[1,2]. The articular cartilage composed of chondrocytes and a dense extracellular matrix (ECM) is a key component of joints that have a limited capacity for intrinsic healing and repair[6,7]. During the progression of OA, active ECM remodeling occurs with environmental changes such as severe or chronic inflammation, which in turn leads to the induction of the maturation of hypertrophic chondrocytes. Hypertrophic chondrocytes characteristically overexpress hypertrophic markers, runt-related transcription factor 2 (RUNX2), Type X collagen, Indian hedgehog, and Transglutaminase-2. Hypertrophic chondrocytes are known to synthesize various matrix-degrading enzymes, such as matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase containing thrombospondin motifs (ADAMTS4, 5), which accelerate the decomposition of the ECM, leading to cartilage loss and calcification[8,9]
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