Bone-derived PDGF-BB drives brain vascular calcification in male mice

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large vessel calcifications in peripheral tissue is well-studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contribute to cerebrovascular calcification in male mice. Aged male mice exhibited higher serum PDGF-BB levels and a significantly higher incidence of brain calcification compared to young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevation of serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA sequencing revealed that PDGF-BB upregulates multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (pPDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of the osteoblast differentiation genes in pericytes and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induces brain vascular calcification by activating the pPDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.