Penetration of the subchondral bone plate allows both the ingrowth of BMSC and the release of growth factors. BMSCs proliferate and contribute to filling of the defect. BMSCs undergo chondrogenic differentiation, which is promoted by factors including Shh, TGFß, FGF18 or GDF5 and mediated by the transcription factors Sox9 and Nkx3.2. Particularly in deeper zones, the cells tend to undergo further terminal differentiation, a process that is mediated by the transcription factors Runx2 and GADD45ß and supported by growth factors including BMPs, Wnts, FGF2 and VEGF. Hypertrophic differentiation is inhibited by factors that are predominantly released by articular chondrocytes including PTHrP, HDAC4, Chm-I, TSP-1 or TIMP- 2/-3. Furthermore, articular cartilage produces GREM1, WISP3 and FRZB, which inhibit BMP and Wnt-signalling. To date it is not known if chondrocyticdifferentiated BMSCs may adopt a permanent articular chondrocyte phenotype.

Figure 3: Extracellular determinants and cellular processes of cartilage repair tissue induced by bone marrow-stimulating techniques.