Role of bone-derived PDGF-BB in age-associated brain calcification

Abstract

Brain vascular calcifications are typically found in the elderly and are associated with various disorders. The mechanisms and primary factors causing this pathological change of brain blood vessel remain largely unknown. Based on previous studies of primary familial brain calcification and neurodegenerative diseases, gene mutations of platelet-derived growth factor B (PDGF-BB) and platelet-derived growth factor receptor β (PDGFRβ) mutation are closely correctly with brain calcification. Recent study from Dr. Wan’s laboratory demonstrated that skeletal pre-osteoclast produce an excessive amount of PDGF-BB into bloodstream during aging. The serum PDGF-BB concentration is increased more than three folds in 22 month-old relative to 3 month-old mice. The serum PDGF-BB concentration is correlated with BBB dysfunction and pericyte loss. In the present study, we investigated the role of pre-osteoclast derived PDGF-BB in the development of brain vascular calcification during aging. Using conditional Pdgfb knock-out (PdgfbcKO) mice, we found that serum PDGF-BB concentration was normalized in aged PdgfbcKO mice relative to age-matched WT littermates. More importantly, brain calcification was not developed in the PdgfbcKO mice as did in the WT mice. We have also established an ex-vivo brain capillary culture system, using which the molecular mechanisms underlying PDGF-BB-induced brain blood vessel calcification was investigated. Our results from the ex vivo experiment suggest that PDGF-BB active osteogenic gene expression of the blood vessel cells, leading to vessel calcification.