PEPITEM and its tripeptide pharmacophores: Mechanisms of bone regulation and therapeutic potential in health and disease

Current osteoporosis therapies are limited by their inability to fully restore bone homeostasis and significant side effects through long-term use. PEPITEM is an endogenous 14 amino acid osteogenic peptide capable of stimulating osteoblast-induced bone formation, whilst simultaneously inhibiting osteoclast-induced bone resorption. Here, we have identified the presence of smaller functional pharmacophores ranging from 3 (SVT, ac-QGA) to 7 (SVTEQGA, LSNEER) amino acids in length that mimic some of the actions of native PEPITEM. Both the N and C-terminal regions of PEPITEM exhibit pro-anabolic and anti-catabolic activity in vitro. Whilst none of the pharmacophores or their peptidomimetics fully recapitulate PEPTIEM dual activity in vivo, enhanced bone formation and reduced resorption was observed in mice with ovariectomy induced osteoporosis in some macro and microscopic assessments. Collectively our data indicate that full-length PEPITEM or pharmacophores encompassing residues from both the N and C-terminus are required to achieve maximal pro-anabolic and anti-catabolic activity. The combination of the dual activity in a naturally occurring peptide with limited potential toxicological profile offers an exciting alternative approach to treating osteoporosis.