Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development
Weiping Su, … , Xu Cao, Mei Wan
Weiping Su, … , Xu Cao, Mei Wan
Published March 24, 2020
Citation Information: JCI Insight. 2020;5(8):e135446. https://doi.org/10.1172/jci.insight.135446.
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Research Article Angiogenesis Bone biology

Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development

Abstract

Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor–BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor–β (PDGFR-β) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence to our knowledge that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.

Authors

Weiping Su, Guanqiao Liu, Xiaonan Liu, Yangying Zhou, Qi Sun, Gehua Zhen, Xiao Wang, Yihe Hu, Peisong Gao, Shadpour Demehri, Xu Cao, Mei Wan

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Figure 5

Transgenic mice expressing PDGF-BB in preosteoclasts recapitulate the pathological features of osteoarthritic joint subchondral bone.

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Transgenic mice expressing PDGF-BB in preosteoclasts recapitulate the pa...
(A) Schematic diagram showing the TRACP5-Pdgfb transgene in the transgenic mice (PdgfbcTG). (B–N) Knee joints were harvested from 5-month-old transgenic mice and WT mice. n = 5 mice per group. Immunofluorescence staining of PDGF-BB (green) and quantification of PDGF-BB+ cells in tibial subchondral bone (B and C). Scale bar: 50 μm. ***P < 0.001. ELISA analysis of PDGF-BB concentration in tibial subchondral bone/bone marrow. ***P < 0.001 (D). Immunofluorescence staining of CD31 (green) and Emcn (red) with quantification of the intensity of CD31hiEmcnhi signal per tissue area in subchondral bone of the tibia (E and F). C, cartilage; SB, subchondral bone. Scale bars: 200 μm (top), 50 μm (bottom). ***P < 0.001. Immunohistochemical analysis of Osterix (brown) and quantification of Osterix+ cells in tibial subchondral bone (G and H). Scale bar: 50 μm.***P < 0.001. Immunofluorescence staining of PGP9.5 (green) with quantification of the intensity of PGP9.5 signal per tissue area in subchondral bone of the tibia (I and J). Scale bar: 50 μm. ***P < 0.001. Three-dimensional μCT images (K) and quantitative analysis of structural parameters of subchondral bone: BV/TV (L), SBP. Th (mm–1) (M), and Tb. Pf (mm–1) (N). *P < 0.05, and **P < 0.01. All data are shown as means ± standard deviations. Statistical significance was determined by unpaired, 2-tailed Student’s t test.