A Small Molecular Kartogenin For Cartilage Repair

Hyaline cartilage injury which includes osteoarthritis (OA) and focal cartilage defect is commonly happening. OA is one of the most common diseases in the elder. OA can lead to severe pain and dysfunction of the joint. The incidence of OA is properly high, especially in the elder more than 60 years old. The rate of OA in people over the age of 65 is 60% in male and 70% in female. With the aged population increasing in society, the incidence of OA will be higher and higher. Focal cartilage defect is common in athletes and young people. According to demorgraphic data, the rate of focal cartilage defect in 40% in athletes. In recent years, the incidence of cartilage defect is increasing as sports activities are more and more popular. There are hundreds million of patients in china, which bring huge economic burden to society. Thus, cartilage injury has become one of the biggest public health problems in the world. There are no effective treatment options for cartilage injury recently. Many patients need joint replacement surgery in the end-stage of the disease. However, the service life of prosthesis is 15 to 20 years. So, many patients need 2 or 3 joint replacement surgery in lifetime. It is meaningful to regenerate hyaline cartilage and restore cartilage injury.It is one of the most difficult problems in orthopaedics to repair cartilage injury and restore smooth joint surface. Currently, the most commonly used treatment options for managing cartilage injuries include microfracture, autologous chondrocyte implantation, and osteochondral transplantation. These procedures can relieve pain and partially restore the function of joints. However, only fibrocartilage which is mechanically weaker than hyaline cartilage and easy to be worn out can be generated. Although no studies have completely replicated the biomechanical qualities of hyaline cartilage, cartilage tissue engineering is still the most promising strategy to restore cartilage injury. It is still necessary to research proper scaffolds, stimulate factors, and a proper way to form engineering cartilage.To solve these problems, we performed three studies. First, we investigate if small molecule KGN can stimulate human synovium derived mesenchymal stem cells into chondrocytes. We separated mesenchymal stem cells from human synovial tissue and used pellets culture system to induce these cells in the presence of small molecule KGN. Our results showed that KGN have synergic effect with TGF-β3 and BMP-2.And, KGN can significantly enhance chondrocytes differentiation and proliferation in a cartilage microenvironment. We found KGN to be a promising additive for directing human SMSCs into chondrocytes. Second, as one of the most commonly used techniques for treating full-thickness cartilage defect, microfracture still have lots of shortcomings. Our previous study demonstrated that KGN can induce human synovium derived mesenchymal stem cells into chondrocytes in vitro. In this study, we want to investigate if KGN can repair cartilage injury in vivo. We made full-thickness cartilage defects in New Zealand White rabbits and performed microfracture procedure. Then KGN was intra-articular injected. The injection procedure was administrated weekly. Outcome was assessed both macroscopically, using an International Cartilage Repair Society (ICRS) macroscopic evaluation system, and histologically, using a modified O’Driscoll histological scoring system. Immunohistochemistry for type II collagen was also conducted. Our results showed that better defects filling and more chondrocyte-like cells were observed in KGN treated animals 4 weeks post operation. And, KGN treated group showed statistically significant higher ICRS score and modified O’Driscoll scores at 12 weeks. Our results showed that intra-articular injection of small molecule KGN may be a promising cartilage defects repair strategy. Third, to get hyaline cartilage in cartilage injury sites, we conducted cartilage tissue engineering study. We construct a KGN sustained hydrogel system which can cross linked quickly under UV light for 30 second. We formed the hydrogel in cartilage defects to recruit mesenchmal stem cells. The results showed that hyaline cartilage like tissue formed in experimental group at both 4 and 12 weeks. While, only some fiber tissue formed in control group.12 weeks post operation, the repair tissue formed in experimental group was even similar with native hyaline cartilage. Our results showed a novel and effective way to restore cartilage defects.