Bone-derived PDGF-BB drives brain vascular calcification in male mice
Jiekang Wang, … , Xu Cao, Mei Wan
Jiekang Wang, … , Xu Cao, Mei Wan
Published October 10, 2023
Citation Information: J Clin Invest. 2023;133(23):e168447. https://doi.org/10.1172/JCI168447.
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Research Article Bone biology Vascular biology

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

Abstract

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 contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated 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-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (p-PDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

Authors

Jiekang Wang, Ching-Lien Fang, Kathleen Noller, Zhiliang Wei, Guanqiao Liu, Ke Shen, Kangping Song, Xu Cao, Mei Wan

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Figure 3

Deletion of Pdgfb from bone preosteoclasts alleviates brain calcification.

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Deletion of Pdgfb from bone preosteoclasts alleviates brain calcificatio...
(A) ELISA measurement of serum PDGF-BB concentrations in 17-month-old PdgfbcKO male mice and WT littermates. n = 4–5. (B) Calculation of the calcification incidence in PdgfbcKO mice and WT littermates based on histology. n = 6. (C) Representative images of Alizarin red– and von Kossa–stained images for 17-month-old PdgfbcKO mice and WT littermates. Calcification nodules are shown in red and black, respectively. Boxed areas are shown at higher magnification (×40) in the corresponding panels on the right. n = 6. (D) Double-immunofluorescence staining of frozen brain tissue sections from 17-month-old PdgfbcKO mice and WT littermates using antibodies against CD13 and OPN. n = 3–4. (E) Quantification of the volume of OPN+ calcified nodules in D. n = 3–4. The Imaris 3D reconstruction method was used to quantify the number and volume of calcification. Scale bars: 100 μm (C and D). Data are shown as the mean ± SD. **P < 0.01 and ***P < 0.001, by unpaired, 2-tailed Student’s t test (A and E).