Skeleton-secreted PDGF-BB mediates arterial stiffening

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

doi:10.1172/jci147116

Cited by 30 publications

(58 citation statements)

References 86 publications

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“…Previous studies identified some molecular lipid species associated with early markers of both osteoporosis and atherosclerosis based on the Young Finns Study cohort, supporting the osteoporosis and atherosclerosis comorbidity hypothesis (14,30). Latest research found that platelet-derived growth factor-BB (PDGF-BB), secreted from preosteoclasts, worked as an important mediator of vascular stiffening in response to aging and metabolic stress (31). Extracellular vesicles derived from aged bone matrix during bone resorption promote bone marrow mesenchymal stem cells adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells (32).…”

Section: Discussionmentioning

confidence: 86%

Integrated Bioinformatic Analysis of the Shared Molecular Mechanisms Between Osteoporosis and Atherosclerosis

Liang

Wang

et al. 2022

Front. Endocrinol.

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BackgroundOsteoporosis and atherosclerosis are common in the elderly population, conferring a heavy worldwide burden. Evidence links osteoporosis and atherosclerosis but the exact underlying common mechanism of its occurrence is unclear. The purpose of this study is to further explore the molecular mechanism between osteoporosis and atherosclerosis through integrated bioinformatic analysis.MethodsThe microarray data of osteoporosis and atherosclerosis in the Gene Expression Omnibus (GEO) database were downloaded. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the co-expression genes related to osteoporosis and atherosclerosis. In addition, the common gene targets of osteoporosis and atherosclerosis were analyzed and screened through three public databases (CTD, DISEASES, and GeneCards). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape. Then, the common microRNAs (miRNAs) in osteoporosis and atherosclerosis were screened out from the Human microRNA Disease Database (HMDD) and the target genes of whom were predicted through the miRTarbase. Finally, the common miRNAs–genes network was constructed by Cytoscape software.ResultsThe results of common genes analysis showed that immune and inflammatory response may be a common feature in the pathophysiology of osteoporosis and atherosclerosis. Six hub genes (namely, COL1A1, IBSP, CTSD, RAC2, MAF, and THBS1) were obtained via taking interaction of different analysis results. The miRNAs–genes network showed that has-let-7g might play an important role in the common mechanisms between osteoporosis and atherosclerosis.ConclusionThis study provides new sights into shared molecular mechanisms between osteoporosis and atherosclerosis. These common pathways and hub genes may offer promising clues for further experimental studies.

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Section: Discussionmentioning

confidence: 86%

Integrated Bioinformatic Analysis of the Shared Molecular Mechanisms Between Osteoporosis and Atherosclerosis

Liang

Wang

et al. 2022

Front. Endocrinol.

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“… 27 Moreover, abnormal overexpression of PDGF-BB in preosteoclasts resulted in vascular and skeletal disorders such as arterial stiffening and OA. 28 , 29 Su W et al recently revealed that excessive secretion of PDGF-BB from preosteoclasts promoted aberrant angiogenesis-dependent bone formation in subchondral bone, leading to OA pathogenesis. 29 , 30 Interestingly, endothelial cell (EC)-specific knockout of PDGFR-β was also reported to affect pathological angiogenesis in tumors but did not affect animal survival or normal tissue functions.…”

Section: Introductionmentioning

confidence: 99%

Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation

Cui

Xiao

et al. 2022

Bone Res

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The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis (OA) remain unknown. No pharmacological intervention can currently prevent the progression of osteoarthritis. Accumulating evidence has shown that subchondral bone deterioration is a primary trigger for overlying cartilage degeneration. We previously found that H-type vessels modulate aberrant subchondral bone formation during the pathogenesis of OA. However, the mechanism responsible for the elevation of H-type vessels in OA is still unclear. Here, we found that PDGFR-β expression, predominantly in the CD31hiEmcnhi endothelium, was substantially elevated in subchondral bones from OA patients and rodent OA models. A mouse model of OA with deletion of PDGFR-β in endothelial cells (ECs) exhibited fewer H-type vessels, ameliorated subchondral bone deterioration and alleviated overlying cartilage degeneration. Endothelial PDGFR-β promotes angiogenesis through the formation of the PDGFR-β/talin1/FAK complex. Notably, endothelium-specific inhibition of PDGFR-β by local injection of AAV9 in subchondral bone effectively attenuated the pathogenesis of OA compared with that of the vehicle-treated controls. Based on the results from this study, targeting PDGFR-β is a novel and promising approach for the prevention or early treatment of OA.

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“…Activation of PDGFR has been involved in VSMC phenotype switching through common transcription factors involved in osteoblast-like phenotype switching, such as Krüppel-like factor (KLF4) ( 37 ). Overexpression of PDGF-B in mice has led to the upregulation of PDGFR, thereby increasing VC through augmentation of Runx2 and ALP ( 38 ). One of the possible mechanisms of PDGFR activation-induced VC is through mitogen-activated protein kinase (MAPK) activation.…”

Section: Role Of Receptor Tyrosine Kinase In Cardiovascular Calcifica...mentioning

confidence: 99%

The two facets of receptor tyrosine kinase in cardiovascular calcification—can tyrosine kinase inhibitors benefit cardiovascular system?

Masbuchin

Widodo

Rohman

et al. 2022

Front. Cardiovasc. Med.

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Tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment due to their effectiveness in cancer cell killing. However, an off-target of this agent limits its success. Cardiotoxicity-associated TKIs have been widely reported. Tyrosine kinase is involved in many regulatory processes in a cell, and it is involved in cancer formation. Recent evidence suggests the role of tyrosine kinase in cardiovascular calcification, specifically, the calcification of heart vessels and valves. Herein, we summarized the accumulating evidence of the crucial role of receptor tyrosine kinase (RTK) in cardiovascular calcification and provided the potential clinical implication of TKIs-related ectopic calcification. We found that RTKs, depending on the ligand and tissue, can induce or suppress cardiovascular calcification. Therefore, RTKs may have varying effects on ectopic calcification. Additionally, in the context of cardiovascular calcification, TKIs do not always relate to an unfavored outcome—they might offer benefits in some cases.

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Skeleton-secreted PDGF-BB mediates arterial stiffening

Cited by 30 publications

References 86 publications

Integrated Bioinformatic Analysis of the Shared Molecular Mechanisms Between Osteoporosis and Atherosclerosis

Integrated Bioinformatic Analysis of the Shared Molecular Mechanisms Between Osteoporosis and Atherosclerosis

Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation

The two facets of receptor tyrosine kinase in cardiovascular calcification—can tyrosine kinase inhibitors benefit cardiovascular system?

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