Osteomodulin positively regulates osteogenesis through interaction with BMP2

Lin, Wei-Ming; Zhu, Xiaohan; Gao, Li; Mao, Mengying; Gao, Daming; Huang, Zhengwei

doi:10.1038/s41419-021-03404-5

Cited by 49 publications

(51 citation statements)

References 53 publications

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“…Although these effects were lost at late stages of the calcification process, likely because SMCs activate other mechanisms to bypass the protective effects of OMD, evidence shows that OMD actively orchestrates the ECM remodelling process at earlier stages. Moreover, vascular calcification recapitulates many features of endochondral ossification, where BMP2 and OMD were recently shown to directly interact 22 . In our study, exogenous BMP2 alone induced osteoblastic reprograming of the cells without yielding significant ECM mineralisation.…”

Section: Discussionsupporting

confidence: 70%

“…It was recently reported that BMP2, involved in vascular calcification by enhancing osteoblast‐like differentiation of vascular SMCs, 39 may be linked with OMD as a positive regulator of osteogenesis through BMP2 signalling in bones. 22 We examined whether BMP2 alone or in combination with rhOMD could be involved in osteoblast differentiation of SMC and matrix calcification after 6 days of treatment. Exogenous administration of BMP2 alone or in combination with rhOMD induced upregulation in mRNA levels of typical SMC markers as well as SMAD3, SP7 and ALPL.…”

Section: Resultsmentioning

confidence: 99%

“… 15 In this regard, results from an unbiased plasma proteomic profiling of a large CVD cohort indicated osteomodulin (OMD, also termed osteoadherin) as one of the potential novel circulating biomarkers associated with cardiovascular risk traits 16 and type 2 diabetes. 17 OMD is a small leucine‐rich keratan sulphate proteoglycan found in the extracellular matrix (ECM) 18 of mineralised tissues, such as bones 19 and teeth, 20 where it is typically expressed by RUNX2 + osteoblasts 21 , 22 and displays a high binding affinity to hydroxyapatite. However, the association of circulating OMD levels with CVD traits is novel 16 , 17 and has yet to be evaluated in independent cohorts, as well as its role in vascular tissue pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

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Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification

Skenteris

Seime

Witasp

et al. 2022

Clinical & Translational Med

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Rationale Vascular calcification is a prominent feature of late‐stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context. Methods and results In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α‐SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE−/− mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β‐glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues. Conclusion We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α‐SMA+ regions of calcified cardiovascular tissues, induced by pro‐inflammatory and pro‐osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.

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Section: Discussionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification

Skenteris

Seime

Witasp

et al. 2022

Clinical & Translational Med

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“…genes were screened out through Cytoscape. Among these 10 upregulated hub genes, most of them such as ALPL, COL4A5 , COL3A1 (Minaříková et al, 2015;Williams et al, 2018), COL11A1 and OMD (Lin et al, 2019(Lin et al, , 2021Ustriyana et al, 2021) are reported to be related to bone mineralization. This result partly proves that DEGs analysis is effective.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Identified miR-584-5p and Key miRNA-mRNA Networks Involved in the Osteogenic Differentiation of Human Periodontal Ligament Stem Cells

et al. 2021

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Human periodontal ligament cells (PDLCs) play an important role in periodontal tissue stabilization and function. In the process of osteogenic differentiation of PDLSCs, the regulation of molecular signal pathways are complicated. In this study, the sequencing results of three datasets on GEO were used to comprehensively analyze the miRNA-mRNA network during the osteogenic differentiation of PDLSCs. Using the GSE99958 and GSE159507, a total of 114 common differentially expressed genes (DEGs) were identified, including 62 up-regulated genes and 52 down-regulated genes. GO enrichment analysis was performed. The up-regulated 10 hub genes and down-regulated 10 hub genes were screened out by protein-protein interaction network (PPI) analysis and STRING in Cytoscape. Similarly, differentially expressed miRNAs (DEMs) were selected by limma package from GSE159508. Then, using the miRwalk website, we further selected 11 miRNAs from 16 DEMs that may have a negative regulatory relationship with hub genes. In vitro RT-PCR verification revealed that nine DEMs and 18 hub genes showed the same trend as the RNA-seq results during the osteogenic differentiation of PDLSCs. Finally, using miR-584-5p inhibitor and mimics, it was found that miR-584-5p negatively regulates the osteogenic differentiation of PDLSCs in vitro. In summary, the present results found several potential osteogenic-related genes and identified candidate miRNA-mRNA networks for the further study of osteogenic differentiation of PDLSCs.

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“…In bone remodeling, the main growth factors are the members of the TGFβ superfamily, mainly bone morphogenetic proteins (BMPs) [10][11][12][13]. The delivery of these factors is a problem not yet solved.…”

Section: Introductionmentioning

confidence: 99%

BMP-2 Delivery through Liposomes in Bone Regeneration

Dîrzu

Lucaciu

Dîrzu³

et al. 2022

Applied Sciences

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Bone regeneration is a central focus of maxillofacial research, especially when dealing with dental implants or critical sized wound sites. While bone has great regeneration potential, exogenous delivery of growth factors can greatly enhance the speed, duration, and quality of osseointegration, making a difference in a patient’s quality of life. Bone morphogenic protein 2 (BMP-2) is a highly potent growth factor that acts as a recruiting molecule for mesenchymal stromal cells, induces a rapid differentiation of them into osteoblasts, while also maintaining their viability. Currently, the literature data shows that the liposomal direct delivery or transfection of plasmids containing BMP-2 at the bone wound site often results in the overexpression of osteogenic markers and result in enhanced mineralization with formation of new bone matrix. We reviewed the literature on the scientific data regarding BMP-2 delivery with the help of liposomes. This may provide the ground for a future new bone regeneration strategy with real chances of reaching clinical practice.

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Osteomodulin positively regulates osteogenesis through interaction with BMP2

Cited by 49 publications

References 53 publications

Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification

Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification

Bioinformatics Analysis Identified miR-584-5p and Key miRNA-mRNA Networks Involved in the Osteogenic Differentiation of Human Periodontal Ligament Stem Cells

BMP-2 Delivery through Liposomes in Bone Regeneration

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