Curcumin Inhibits Chondrocyte Hypertrophy of Mesenchymal Stem Cells through IHH and Notch Signaling Pathways

Abstract

Using tissue engineering technique to repair cartilage damage caused by osteoarthritis is a promising strategy. However, the regenerated tissue usually is fibrous cartilage, which has poor mechanical characteristics compared to hyaline cartilage. Chondrocyte hypertrophy plays an important role in this process. Thus, it is very important to find out a suitable way to maintain the phenotype of chondrocytes and inhibit chondrocyte hypertrophy. Curcumin deriving from turmeric was reported with anti-inflammatory and antitumor pharmacological effects. However, the role of curcumin in metabolism of chondrocytes, especially in the chondrocyte hypertrophy remains unclear. Mesenchymal stem cells (MSCs) are widely used in cartilage tissue engineering as seed cells. So we investigated the effect of curcumin on chondrogenesis and chondrocyte hypertrophy in MSCs through examination of cell viability, glycosaminoglycan synthesis and specific gene expression. We found curcumin had no effect on expression of chondrogenic markers including Sox9 and Col2a1 while hypertrophic markers including Runx2 and Col10a1 were down-regulated. Further exploration showed that curcumin inhibited chondrocyte hypertrophy through Indian hedgehog homolog (IHH) and Notch signalings. Our results indicated curcumin was a potential agent in modulating cartilage homeostasis and maintaining chondrocyte phenotype.Key words curcumin; mesenchymal stem cell; chondrocyte hypertrophy; Indian hedgehog homolog; neurogenic locus notch homolog Osteoarthritis (OA) is a degenerative joint disease accompanied by pain and disability.1) Seventy percent of the population older than 65 years is suffering from varying degrees of OA.2)The pathogenesis of cartilage injury caused by OA is the disruption of the homeostasis between catabolism and anabolism of extracellular matrix.3) However, limited by the intrinsic regeneration capacity of cartilage tissue, repairing damaged articular cartilage currently is a significant challenge. 4,5) With the advances in materials science, cell biology, biomechanics, using tissue engineering technology to construct cartilage provides a novel method for repairing damaged cartilage.6) Mesenchymal stem cells (MSCs) have potential of differentiation into chondrocytes and have got the priority in the seed cells choosing list because of their traits in rich resources, easy to get and low immunogenicity. 7,8) However, the regenerated tissue-engineered cartilage usually is fibrous cartilage rather than hyaline cartilage.9) The chondrocytes in fibrous cartilage proceed in hypertrophic differentiation and secret Col10a1 and matrix metalloproteinase 13 (Mmp13).10) Therefore, suppressing chondrocyte hypertrophy is the key issue to build a stable hyaline cartilage.Curcumin is effective substance of turmeric and possesses various pharmacological effects, including antioxidant, anti-bacterial, anti-tumor and anti-inflammatory.11-13) A recent study has reported that curcumin may be a potential therapeutic candidate for Helicobacter pylori associated diseas...

Evaluation of the articular cartilage in the knees of rats with induced arthritis treated with curcumin

“…Van der Kraan and Van den Berg [55] suggested a correlation between IHH expression and the progression of OA in animal models, due to protease-mediated effects on the progression of OA. As shown in the study by Cao et al [52], curcumin effectively reduces IHH expression in chondrocytes and mesenchymal stem cells, inhibiting GLI2 gene expression and increasing GLI3 expression to subsequently modulate cartilage homeostasis and maintain chondrocyte phenotypes, which corroborated the histological findings from the present study.…”

“…Our results may be complementary, as we showed an increased number of chondrocytes in the surface layer of the COAG compared to that in the OAG as well as an increased number of chondrocytes in the middle layer of the OAG and COAG compared to that in the CG. According to Cao et al [52], curcumin inhibits chondrocyte hypertrophy by decreasing IHH expression. Moreover, curcumin also reduces matrix degradation in the cartilage by balancing the anabolic and catabolic activity of repair cells [53],inhibits the effects of sodium nitroprusside (SNP) on inducing chondrocyte apoptosis, and maintains the balance of extracellular matrix metabolism [28].…”

The Efficacy and Safety of Highly-Bioavailable Curcumin for Treating Knee Osteoarthritis: A 6-Month Open-Labeled Prospective Study

“…Curcumin was a potential agent in modulating cartilage homeostasis and maintaining the chondrocyte phenotype. 31 However, although this study was unable to demonstrate improvements in patient knee cartilage, the above findings suggest that curcumin might improve the knee cartilage of such patients.…”

Functional Duality of Chondrocyte Hypertrophy and Biomedical Application Trends in Osteoarthritis

“…In addition to the artificial chemical cues, the chemical cues present in nature were also assessed for their effects against chondrocyte hypertrophy. Curcumin has been reported to have anti-inflammatory and anti-tumor effects, and it inhibits chondrocyte hypertrophy through the IHH and Notch signaling pathways [ 127 ]. Cordycepin is a nucleoside adenosine, which has antioxidant and anti-inflammatory effects, and it has been reported that cordycepin inhibits chondrocyte hypertrophy though PI3K/Bapx1 and Notch signaling [ 128 ].…”