Figure 2.

Signaling pathways of Pln and effect on cartilage development. (A) FGF signaling and mechanotransduction role. The role Pln plays in regulating cartilage homeostasis is achieved by the formation of the PlnDI-FGF complex. This complex sequesters FGFs from receptors on the cell surface and inhibits the downstream signaling pathway [48,93,135–137]. FGF-2 also plays a mechanotransduction role in cartilage via influencing the ERK signaling pathway [15,84,134,139]. (B) BMP signaling. The roles that BMP signaling plays in chondrogenesis and osteogenesis are regulated by BMP-2 storage in the PlnDI-BMP complex and the delicate balance between ligands and antagonists [143–147,149]. (C) CTGF signaling. The interaction between CTGF and PlnDII triggers various intracellular signaling pathways and thus regulates the proliferation and maturation of chondrocytes [29,121,151,152,154,155]. (D) FAK-Src signaling. PlnDIV prevents early cell attachment and promotes cell clustering/condensation by suppressing the FAK/Src signaling pathway, but the receptor is unknown [37,156,157]. (E) VEGF signaling. In the early stage of cartilage development, PlnDI, unbound or bound to VEGF165, stimulates angiogenesis by direct interactions with neuropilin 1 (NRP1), VEGFR2, and NRP1/VEGFR2 co-receptors [164]. In the later stage of cartilage development, PlnDV inhibits angiogenesis via dual receptor VEGF2 and integrin. The endorepellin-induced dual receptor internalization and degradation by the caveosome-mediated pathway is also involved in angiostasis [163,165,171].