The Basic Study For Optimized Delivery Of FGF2 To Promote The Repair Of Articular Cartilage

Articular cartilage is an avascular tissue that has only limited capacity for self-repair. Various growth factors involved in the development and regeneration of articular cartilage are also widely used in the study of articular cartilage repair. In particular, our group previously found that spatiotemporal controlled delivery of fibroblast growth factor 2 (FGF2) accelerated the articular cartilage regeneration. However, question remains to be solved in order to optimize the application of FGF2 in articular cartilage repair, for example, the mechanism, the targeted tissue or cell, the combined application with other growth factor, and so on. We believe answers to these problems will provide new ideas on rational application of FGF2 in articular cartilage repair, and also benefit for understanding the mechanism of articular cartilage repair.In this thesis, the molecular mechanisms of FGF2 in articular cartilage repair, as well as the effects of other relevant growth factors in articular cartilage repair were investigated. Then, the effects of FGF2 on different tissues and cells involving in articular cartilage repair, including cartilage, subchondral bone, chondrocyte and bone marrow mesenchymal stem cells (BMSCs) were demonstrated, according to which the targeted tissue or cell of FGF2 for targeting delivery was analyzed. In addition, the effects of insulin-like growth factor 1 (IGF1) on articular cartilage repair were studied. Finally, the possibility for the combined application of FGF2 and IGF1 in articular cartilage repair was discussed. The main results and conclusions of this work are as follows:1. Cartilage layer modulated by FGF2 displays limited chondrogenic potential. FGF2 accelerates the degradation of extracellular matrix in cartilage, inhibits the expression of endogenous growth factors for chondrogenesis, and induces the formation of fibrocartilage. These all impede the articular cartilage repair, indicating cartilage layer or chondrocyte is not the effective target of FGF2.2. Subchondral bone plate can be effectively modulated by FGF2. The expressions of bone morphogenetic protein 2 (BMP2), BMP4 and SOX9 of subchondral bone, critical growth factors and transcription factor for chondrogenesis, are up-regulated by FGF2. These findings indicate that subchondral bone is the effective target tissue of FGF2, and BMP signaling pathway may play critical roles in articular cartilage repair.3. Subchondral bone plays an important role in articular cartilage repair. The structure deterioration and activity inhibition of the subchondral bone by BMP3 impairs the repair of articular cartilage defect in rabbit. Since BMP3 is an inhibitor of BMP signaling, these data confirm that subchondral bone and BMP signaling play critical roles in articular cartilage repair. Additionally, BMP3 shows no effects on repair of partial-thickness articular cartilage defect, but induces the degradation of extracellular matrix and interfere with the survival of chondrocyte surrounding the defect.4. IGF1 is beneficial to articular cartilage repair when it acts on cartilage and chondrocyte. In particular, IGF1 can exert the protective roles by aiding chondrocyte survival and preserving the structural integrity of extracellular matrix at the early stage during the articular cartilage repair.Above all, we investigated the effects and mechanisms of FGF2, BMP3 and IGF1 on articular cartilage repair. We find that subchondral bone plays important roles in articular cartilage repair. Particularly, the mechanisms underlying FGF2-activated BMP signaling of subchondral bone is essential for articular cartilage repair. Additionally, the protective role of IGF1 on cartilage or chondrocyte is beneficial for the integrity of neo-cartilage and articular cartilage repair. Thus, our findings may advance the understanding of mechanism on growth factors in osteochondral repair, and provide the basis for the FGF2 targeted delivery in treatment of articular cartilage defect.