Skeleton-secreted PDGF-BB mediates arterial stiffening
Lakshmi Santhanam, … , Xu Cao, Mei Wan
Lakshmi Santhanam, … , Xu Cao, Mei Wan
Published August 26, 2021
Citation Information: J Clin Invest. 2021;131(20):e147116. https://doi.org/10.1172/JCI147116.
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Research Article Bone biology Vascular biology

Skeleton-secreted PDGF-BB mediates arterial stiffening

Abstract

Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor–BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.

Authors

Lakshmi Santhanam, Guanqiao Liu, Sandeep Jandu, Weiping Su, Bulouere P. Wodu, William Savage, Alan Poe, Xiaonan Liu, Lacy M. Alexander, Xu Cao, Mei Wan

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Figure 1

Aged mice and HFD-challenged mice develop low bone mass and an arterial stiffening phenotype.

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Aged mice and HFD-challenged mice develop low bone mass and an arterial ...
(A–E) Representative μCT images (A) and quantitative analysis (B–E) of the trabecular bone area of the distal femur from 4- and 20-month-old male C57BL/6 mice. Bone volume per tissue volume (BV/TV) (B), trabecular bone thickness (Tb.Th) (C), trabecular bone number (Tb.N) (D), and trabecular bone separation (Tb.Sp) (E). (F and G) Pulse-wave velocity (PWV) and systolic, diastolic, and mean blood pressure (BP) measurements of 4- and 20-month-old male mice. (H–L) Representative μCT images (H) and quantitative analysis (I–L) of the trabecular bone area of the distal femur from 3-month-old male C57BL/6 mice fed a Western HFD or normal CHD for 5 months. BV/TV (I), Tb.Th (J), Tb.N (K), and Tb.Sp (L). (M and N) PWV and BP measurements of the mice fed HFD or CHD. n = 5 to 9. Data are mean ± SD, *P < 0.05, *P < 0.01, ***P < 0.005, as determined by Student’s t tests.