Elevated PDGF‐BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRβ Shedding from Pericytes

Abstract

Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in bone is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB in aged mice and high-fat diet (HFD)-challenged mice correlates with capillary reduction, pericyte loss, and increased blood-brain barrier (BBB) permeability in their hippocampus.

Neural stem cells protect blood-brain barrier integrity via the p38, JNK, and ERK1/2 pathways following intracerebral hemorrhage in rats

“…Second, our study focused on the effect of NSCs on TJPs in the BBB. Other microvascular structural components, such as astrocytic end-feet and pericytes, are also pertinent to BBB integrity and may be impacted by NSCs treatment 50 . Third, there are several alternative mechanisms by which NSCs could impact BBB permeability that were not explored, including via antioxidative effects.…”

Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome

“…C57BL/6 conditional Pdgfb knockout (pdgfb cKO ) and Pdgfb transgenic male mice (pdgfb cTG ) were generated as previously described [ 6 , 7 , 26 ]. Briefly, Pdgfb f/f mouse strain was purchased from Jackson Laboratory (Bar Harbor, ME, USA).…”

“…Many studies have shown that metabolic stress, especially high-fat diet (HFD) challenge, exacerbates neuroinflammation and cognitive decline [ 3 – 5 ]. Our previous work also demonstrated that HFD promotes preosteoclast senescence and platelet-derived growth factor-BB (PDGF-BB) secretion into the circulation, which is one of the cause for microvascular impairment [ 6 , 7 ]. However, how PDGF-BB secretion induced by HFD challenge impairs brain function and the mechanism of the bone-brain axis participation in metabolic stress-induced brain vascular impairment remain unknown.…”

“…Meanwhile, several studies have shown that the plasma levels of C-C motif chemokine ligand 1 (CCL-1), C-C motif chemokine ligand 2 (CCL-2), and vascular cell-adhesion molecule 1 (VCAM-1) are positively correlated with neurodegenerative disorder [ 23 – 25 ], indicating that circulating factors are important factors affecting brain homeostasis. Our previous work demonstrated that, as a new pro-aging factor, senescent preosteoclast-secreted PDGF-BB is elevated in the plasma and may cause pericyte loss during aging and HFD challenge [ 6 ]. However, whether PDGF-BB participates in HFD-induced neuroinflammation and how PDGF-BB-associated neuroinflammation induces a transcytosis shift and BBB leakage under HFD challenge remains to be determined.…”

Focus on senescence: Clinical significance and practical applications

“…A standardized set of bone/bone marrow senescence/SASP-associated factors and genes, named SenMayo [57], has been recently formulated to inform about the specificity of senescencerelated factors and their applicability across tissues and species for senotherapeutic therapies. For instance, the secretion of platelet-derived growth factor-BB by senescent [58] preosteoclasts manifests as a systemic pro-aging factor, contributing to the age-associated increase in arterial stiffness and cerebrovascular impairment [59].…”