Figure 2.

Vitamin K-dependent pathways in skeletal biology. Vitamin K applies multiple molecular pathways in order to affect skeletal biology: I.: Vitamin K may affect cartilage and bone by binding to cell surface receptors, such as the pregnane X receptor. This results in the modulation of downstream signaling pathways ultimately modifying gene expression (e.g., of Msx2). II.: Vitamin K may exert actions on skeletal tissues by acting as a co-factor in the γ-carboxylation of VKDPs. VDKPs, in turn, apply further pathways to affect cartilage and bone biology: (A) Through their Gla-residues VKDPs can bind to calcium crystals and thereby modulate calcification processes in bone and soft tissues. This has been particularly investigated for osteocalcin, MGP, and Ucma. (B) The second mode of action of VKDPs is the interaction with extracellular matrix proteins, supporting the organization of the ultrastructural matrix architecture (shown, e.g., for periostin and suspected for Ucma/GRP). (C) Inhibition of matrix proteases has been shown for Ucma/Grp and mediates a protective effect of Ucma/GRP against cartilage matrix degradation. (D) Finally, hormone-like effects of osteocalcin have been shown to mediate crosstalk between bone and glucose metabolism. ECM: extracellular matrix; Postn: periostin; ProtS: protein S; VitK: Vitamin K; X: downstream target gene/protein of Vitamin K.