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 3

Bone/bone marrow preosteoclasts in aged mice and HFD mice are a main source of elevated circulating PDGF-BB.

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Bone/bone marrow preosteoclasts in aged mice and HFD mice are a main sou...
(A and B) Immunofluorescence staining of femoral bone tissue from 3- and 20-month-old mice. Representative PDGF-BB staining image (A) and quantitative analysis of the number of PDGF-BB+ cells per tissue area (B). (C and D) Frozen femoral bone (C) and aorta tissue sections (D) from TRAP/tdTom mice were subjected to immunofluorescence staining using specific PDGF-BB antibody. Fluorescence imaging of tdTom+ cells (red), PDGF-BB+ cells (green), and double positive cells (yellow) are shown. (E–H) Measurement of Pdgfb mRNA in bone/bone marrow preosteoclasts. Diagram showing the procedure for the isolation of bone/bone marrow cells from femoral bone using our previously described approach (E) (also see description in Methods). Cell suspension collected from TRAP/tdTom mice with CHD and HFD was subject to FACS to isolate tdTom+ cells. mRNA expression levels of Pdgfb were measured by qRT-PCR (F). Cell suspension collected from C57B/L6 mice was subject to FACS to isolate CD3/B220/T119–RANK+ cells. The mRNA levels of Pdgfb in aged mice versus young mice (G) and HFD mice versus CHD mice (H) were measured by qRT-PCR. n = 5. Data are mean ± SD. *P < 0.001, as determined by Student’s t tests.