In Vivo Identification and Induction of Articular Cartilage Stem Cells by Inhibiting NF-κB Signaling in Osteoarthritis

Abstract

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder characterized by the degeneration of articular cartilage. However, no effective medical therapy has been found yet for such condition. In this study, we directly confirmed the existence of articular cartilage stem cells (ACSCs) in vivo and in situ for the first time both in normal and OA articular cartilage, and explored their chondrogenesis in Interleukin-1b (IL-1b) induced inflammation environment and disclose whether the inhibition of NF-jB signaling can induce ACSCs activation thus improve the progression of experimental OA. We found an interesting phenomenon that ACSCs were activated and exhibited a transient proliferative response in early OA as an initial attempt for selfrepair. During the in vitro mechanism study, we discovered IL-1b can efficiently activate the NFjB pathway and potently impair the responsiveness of ACSCs, whereas the NF-jB pathway inhibitor rescued the ACSCs chondrogenesis. The final in vivo experiments further confirmed ACSCs' activation were maintained by NF-jB pathway inhibitor, which induced cartilage regeneration, and protected articular cartilage from injury in an OA animal model. Our results provided in vivo evidence of the presence of ACSCs, and disclosed their action in the early OA stage and gradual quiet as OA process, presented a potential mechanism for both cartilage intrinsic repair and its final degradation, and demonstrated the feasibility of inducing endogenous adult tissuespecific mesenchymal stem cells for articular cartilage repair and OA therapy. STEM CELLS 2015;33:3125-3137 SIGNIFICANCE STATEMENTThe study confirmed the existence of articular cartilage stem cells (ACSCs) in vivo and in situ for the first time both in normal and OA articular cartilage, found an interesting phenomenon that ACSCs were activated and exhibited a transient proliferative response in early OA as an initial attempt for self-repair, confirmed ACSCs' activation were maintained by NF-jB pathway inhibitor, which induced cartilage regeneration, and protected articular cartilage from injury in an OA animal model, demonstrated the feasibility of inducing endogenous adult tissue-specific mesenchymal stem cells for articular cartilage repair and OA therapy.

BMSCs‐Derived Exosomes Ameliorate Pain Via Abrogation of Aberrant Nerve Invasion in Subchondral Bone in Lumbar Facet Joint Osteoarthritis

“…OA is the most frequent form of arthritis, characterized by progressive degenerations in articular cartilage and chronic joint pain . Owing to the limited understanding of the pathogenesis of OA, an urgent improvement for prevention and therapy is required in clinical practice.…”

“…OA is the most frequent form of arthritis, characterized by progressive degenerations in articular cartilage and chronic joint pain. 31,32 Owing to the limited understanding of the pathogenesis of OA, an urgent improvement for prevention and therapy is required in clinical practice. Here, we provided the first evidence that exosomesomes from BMSCs can attenuate cartilage degeneration and relieve the chronic pain in the preclinical models of LFJ-OA.…”

LncRNA GAS5 Overexpression Reverses LPS-Induced Inflammatory Injury and Apoptosis Through Up-Regulating KLF2 Expression in ATDC5 Chondrocytes

“…Osteoarthritis (OA), characterized by degradation of articular cartilage, appears to affect over 43 million people around the world, 63% of whom are 60 years of age or older [1,2]. As the most common form of arthritis, OA is related to a myriad of risk factors, such as ageing, obesity, acetabular dysplasia and genetics [3][4][5].…”

ILKAP Binding to and Dephosphorylating HIF-1α is Essential for Apoptosis Induced by Severe Hypoxia

“…For western blot analysis, 15 µg sample was resolved by 12% SDS-polyacrylamide gel electrophoresis (PAGE) and electrotransferred onto a nitrocellulose membrane (Whatman, Piscataway, NJ) [14]. The primary antibodies used were anti-HIF-1α, anti-ILKAP, and anti-p53 from Novus Biologicals (Littleton, CO), and anti-cleaved caspase-3, anti-cleaved caspase-7, and anti-cleaved caspase-8 from Cell Signaling Technology (Danvers, MA) at a dilution of 1: 500.…”