Boning up on DPP4, DPP4 substrates, and DPP4-adipokine interactions: Logical reasoning and known facts about bone related effects of DPP4 inhibitors.

Dipeptidyl peptidase 4 (DPP4) is a conserved exopeptidase with an important function in protein regulation. The activity of DPP4, an enzyme which can either be anchored to the plasma membrane or circulate free in the extracellular compartment, affects the glucose metabolism, cellular signaling, migration and differentiation, oxidative stress and the immune system. DPP4 is also expressed on the surface of osteoblasts, osteoclasts and osteocytes, and was found to play a role in collagen metabolism. Many substrates of DPP4 have an established role in bone metabolism, among which are incretins, gastrointestinal peptides and neuropeptides. In general, their effects favor bone formation, but some effects are complex and have not been completely elucidated. DPP4 and some of its substrates are known to interact with adipokines, playing an essential role in the energy metabolism. The prolongation of the half-life of incretins through DPP4 inhibition led to the development of these inhibitors to improve glucose tolerance in diabetes. Current literature indicates that the inhibition of DPP4 activity might also result in a beneficial effect on the bone metabolism, but the long-term effect of DPP4 inhibition on fracture outcome has not been entirely established. Diabetic as well as postmenopausal osteoporosis is associated with an increased activity of DPP4, as well as a shift in the expression levels of DPP4 substrates, their receptors, and adipokines. The interactions between these factors and their relationship in bone metabolism are therefore an interesting field of study.