Targeting inflammatory processes for optimization of cartilage homeostasis and repair techniques

Abstract

The outcome of cartilage repair techniques is often hampered by unwanted ossification (e.g. intralesional osteophytes) at the site of the repaired cartilage. Furthermore, stimulating progenitor cells towards chondrocytes and locking them in their desired state is another important hinge point in cartilage repair techniques. Studying the cartilage formation process by endochondral ossification may provide important clues which further enhance cartilage repair techniques in general and may provide crucial information to prevent unwanted ossification in particular. During endochondral ossification mesenchymal progenitors differentiate into proliferative chondrocytes which gradually further differentiate into hypertrophic chondrocytes and finally die by apoptosis; the remaining scaffold is mineralised towards bone. This process takes place in growth plates, during fracture healing and in part during development of articular cartilage, where the endochondral ossification halts at the chondrogenic phase. While inflammation is generally regarded as a negative factor for joint homeostasis and cartilage development, it is also known that inflammation is the first and essential phase of tissue repair in general and bone fracture healing via endochondral ossifcation indeed also depends on haematoma formation and subsequent inflammatory microenvironment. Recently, a growing body of experimental evidence has been published, showing that inflammatory molecules (e.g. NF-κB, COX-2, iNOS, TNFα, interleukins) and their down-stream pathways are not only associated with cartilage degeneration, but are also crucially involved in the initiation of the chondrogenic differentiation process and regulation of cartilage hypertrophy and mineralization. The data described in these reports suggest that one could use these inflammatory pathways for cartilage regenerative medicine, as the initiation of chondrogenic differentiation is a crucial moment for progenitor cell-based cartilage repair techniques. Furthermore, targeting inflammatory mediators may also provide a potential pharmacological approach to prevent or decrease chondrocyte hypertrophic differentiation and subsequent bone formation (e.g. intralesional osteophytes) in cartilage repair techniques. This chapter describes important characteristics of hyaline articular cartilage, drawbacks of current cartilage repair techniques, the process of endochondral ossification and how inflammation related molecules are involved in different phases of endochondral ossification. In addition, this chapter discusses how better insight into these pathways may provide novel molecular tools to modulate chondrogenesis in cartilage regenerative medicine.