Enhancement of the chondrogenic differentiation of mesenchymal stem cells and cartilage repair by ghrelin

Abstract

Transforming growth factor beta (TGF‐β) is commonly utilized in chondrogenic differentiation protocols, but this often results in incomplete maturation of the derived chondrocytes. Gene expression analysis, quantitation of sulfated glycosaminoglycan and collagen, and histological staining were performed to assess the effects of ghrelin. The signaling pathways involved were investigated with inhibitors or targeted by shRNAs. Joint cavity delivery of TGF‐β with or without ghrelin, within a rat cartilage defect model was performed to evaluate the in vivo effects of ghrelin. Ghrelin dramatically enhanced gene expression levels of SOX9, ACAN, and COL II and resulted in increased synthesis of sulfated glycosaminoglycan (sGAG) and collagen in vitro. Combined treatment with TGF‐β and ghrelin synergistically enhanced the phosphorylation of ERK1/2 and DMNT3A, which accounted for increased expression of chondrogenic genes. Delivery of ghrelin in combination with TGF‐β after MSC implantation within a rat osteochondral defect model significantly enhanced de novo cartilage regeneration, as compared to delivery with TGF‐β alone. In conclusion, ghrelin could significantly enhance MSC chondrogenic differentiation in vitro and can also enhance cartilage regeneration in vivo when used in combination with TGF‐β. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1387–1397, 2019.

The clinical efficacy of arthroscopic therapy with knee infrapatellar fat pad cell concentrates in treating knee cartilage lesion: a prospective, randomized, and controlled study

“…Instead of being cultured as in other studies, the cell concentrates containing MSCs were injected into the joint cavity directly during arthroscopy surgery. It is widely believed that culture microenvironment can affect the differentiation of MSCs [27,28,[42][43][44][45][46], and the culturing process can add the risk of infection. According to the studies, it is known that the proliferation and differentiation of MSCs can be influenced by the paracrine effects of the cytokines and growth factors released by the grafted cells, which can trigger host-associated signaling pathways, increase angiogenesis, and decrease apoptosis.…”

Dual Delivery of TGF-β3 and Ghrelin in Microsphere/Hydrogel Systems for Cartilage Regeneration

“…The lowest tested dose of 1 nM ghrelin significantly increased the gene expression levels of SOX9, COL II and ACAN. Ghrelin at other concentrations had a weaker synergistic effect on chondrogenic differentiation [ 13 ]. In this study, we continued to explore the effect of the combination of lower concentrations of ghrelin (1, 0.1 and 0.01 nM) and TGF-β3 (10 ng/mL and 1 ng/mL) on chondrogenic differentiation.…”

“…Ghrelin is a polypeptide hormone mainly derived from the stomach and is the first endogenous ligand of growth hormone secretagogue receptor-1a (GHSR-1A) discovered so far [ 12 ]. We just found that ghrelin significantly enhances chondrogenic differentiation both in vitro and in vivo in conjunction with TGF-β3 [ 13 ]. Although hydrogels can deliver growth factors, the hydrophilicity of hydrogels makes the release of hydrophilic molecules too fast.…”

Clinical Efficacy of Arthroscopic Therapy With Infrapatellar Fat Pad Cell Concentrates in Treating Knee Cartilage Lesion: a Randomized Controlled Trial

“…Instead of being cultured like other research, cell concentrates containing MSCs were injected into the corresponding joint cavity directly during the arthroscopy surgery. It is widely believed that local microenvironment during culture can affect the differentiation of MSCs [27,28,[42][43][44][45][46], and the culturing process can add the risk of infection. According to the studies, it is known that the proliferation and differentiation of MSCs can be in uenced by the paracrine effects of the cytokines and growth factors released by the grafted cells, which can trigger host-associated signaling pathways, increase angiogenesis, and decrease apoptosis.…”