Skeleton-secreted PDGF-BB mediates arterial stiffening
Lakshmi Santhanam, Guanqiao Liu, Sandeep Jandu, Weiping Su, Bulouere P. Wodu, William Savage, Alan Poe, Xiaonan Liu, Lacy M. Alexander, Xu Cao, Mei Wan
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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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.