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miR-188-3p targets skeletal endothelium coupling of angiogenesis and osteogenesis during ageing

He, Wen-Zhen, Yang, Mi, Jiang, Yangzi, He, Chen, Sun, Yu-Chen, Liu, Ling, Huang, Mei, Jiao, Yu-Rui, Chen, Kai-Xuan, Hou, Jing, Huang, Min, Xu, Yi-Li, Feng, Xu, Liu, Ya, Guo, Qi, Peng, Hui, Huang, Yan, Su, Tian, Xiao, Ye, Li, Yusheng, Zeng, Chao, Lei, Guanghua, Luo, Xiang-Hang, Li, Chang-Jun·2022·Cell Death & Disease
DOI 10.1038/s41419-022-04902-wPMC PMC9130327
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Abstract

A specific bone capillary subtype, namely type H vessels, with high expression of CD31 and endomucin, was shown to couple angiogenesis and osteogenesis recently. The number of type H vessels in bone tissue declines with age, and the underlying mechanism for this reduction is unclear. Here, we report that microRNA-188-3p (miR-188-3p) involves this process. miRNA-188-3p expression is upregulated in skeletal endothelium and negatively regulates the formation of type H vessels during ageing. Mice with depletion of miR-188 showed an alleviated age-related decline in type H vessels. In contrast, endothelial-specific overexpression of miR-188-3p reduced the number of type H vessels, leading to decreased bone mass and delayed bone regeneration. Mechanistically, we found that miR-188 inhibits type H vessel formation by directly targeting integrin β3 in endothelial cells. Our findings indicate that miR-188-3p is a key regulator of type H vessel formation and may be a potential therapeutic target for preventing bone loss and accelerating bone regeneration.

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Figures

Fig. 1 miR-188 knockout mice showed an alleviated decline in type H vessels with age. A Representative images of coimmunostaining of Emcn (red) and CD31 (green) in femur sections from 1-month-, 6-month-, and 15-month-old WT and miR-188 knockout (Mir188−/−) mice. Scale bar = 100 µm. B Quantification of type H vessels in femur sections from 1-month-, 6-month-, and 15-month-old WT and Mir188−/− mice. n = 4 mice in each group. C Representative images of Flow-cytometry analysis dot plot from the long bones of 1-month-, 6-month-, and 15-month-old WT and Mir188−/− mice. D Quantitative flow-cytometry analysis of CD31high and Emcnhigh cells from the long bones of 1-month-, 6-month-, and 15-month-old WT and Mir188−/− mice. n = 3 (1-month Mir188−/− mice and 6-month WT mice), n = 4 (1-month WT mice, 6-month Mir188−/− mice, 15-month WT mice and 15-month Mir188−/− mice). gp growth plate, mp metaphysis, mo month. Data are shown as the mean ± SD. n.s. no significance; **P < 0.01 by Student’s t test.
Fig. 1 miR-188 knockout mice showed an alleviated decline in type H vessels with age. A Representative images of coimmunostaining of Emcn (red) and CD31 (green) in femur sections from 1-month-, 6-month-, and 15-month-old WT and miR-188 knockout (Mir188−/−) mice. Scale bar = 100 µm. B Quantification of type H vessels in femur sections from 1-month-, 6-month-, and 15-month-old WT and Mir188−/− mice. n = 4 mice in each group. C Representative images of Flow-cytometry analysis dot plot from the long bones of 1-month-, 6-month-, and 15-month-old WT and Mir188−/− mice. D Quantitative flow-cytometry analysis of CD31high and Emcnhigh cells from the long bones of 1-month-, 6-month-, and 15-month-old WT and Mir188−/− mice. n = 3 (1-month Mir188−/− mice and 6-month WT mice), n = 4 (1-month WT mice, 6-month Mir188−/− mice, 15-month WT mice and 15-month Mir188−/− mice). gp growth plate, mp metaphysis, mo month. Data are shown as the mean ± SD. n.s. no significance; **P < 0.01 by Student’s t test.CC BY · PubMed Central
Fig. 2 miR-188-3p expression increased during senescence and inhibited angiogenesis in vitro. A The expression of miR-188-3p in primary endothelial progenitor cells from the age-indicated male C57BL/6 mice. n = 3 in each group. B Representative images of β-gal staining from HMEC-1 treated with PBS or H2O2. Scale bar = 200 µm. C–G The relative expression of Ink4a-p16 and SASP factors (IL-1, IL-6, IL-8, TNF-a) in the HMEC-1 cells treated with PBS or H2O2. n = 3 in each group. H–K Images of western blotting (H) and quantitative analysis of P53, P-P53, γ-H2AX protein expression levels (I–K) in the HMEC-1 cells treated with PBS or H2O2. n = 3 in each group. L The expression of miR-188-3p in HMEC-1 treated with PBS or H2O2. n = 3 in each group. M Representative images of tube formation assays from the groups transfected with miR-188-3p mimics or miRNA-NC. Scale bar = 500 μm. N, O Quantification of tube junction numbers (N) and total master segment length (O) in the tube formation assays of the indicated groups. n = 3 miR-188-3p mimic-treated groups, n = 4 miRNA-NC-treated groups. P, Q Representative images (P) and wound healing percentage (Q) of the endothelial cell line transfected with miR-188-3p or miRNA-NC in the wound healing assays. Scale bar = 500 μm. n = 3 in each group. R, S Representative images (R) and quantitative analysis (S) of the migrated cells from a Transwell migration assay. Scale bar = 500 μm. n = 4 miR-188-3p-treated group, n = 5 miRNA-NC-treated group. T, U The relative expression of Emcn (T) and CD31 (U) in the HMEC-1 cells transfected with miR-188-3p mimics or miRNA-NC. n = 3 in each group. NC: treated with miRNA-NC, miR-188-3p mimics: treated with miR-188-3p mimics. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by two-tailed Student’s t test or Welch’s t test.
Fig. 2 miR-188-3p expression increased during senescence and inhibited angiogenesis in vitro. A The expression of miR-188-3p in primary endothelial progenitor cells from the age-indicated male C57BL/6 mice. n = 3 in each group. B Representative images of β-gal staining from HMEC-1 treated with PBS or H2O2. Scale bar = 200 µm. C–G The relative expression of Ink4a-p16 and SASP factors (IL-1, IL-6, IL-8, TNF-a) in the HMEC-1 cells treated with PBS or H2O2. n = 3 in each group. H–K Images of western blotting (H) and quantitative analysis of P53, P-P53, γ-H2AX protein expression levels (I–K) in the HMEC-1 cells treated with PBS or H2O2. n = 3 in each group. L The expression of miR-188-3p in HMEC-1 treated with PBS or H2O2. n = 3 in each group. M Representative images of tube formation assays from the groups transfected with miR-188-3p mimics or miRNA-NC. Scale bar = 500 μm. N, O Quantification of tube junction numbers (N) and total master segment length (O) in the tube formation assays of the indicated groups. n = 3 miR-188-3p mimic-treated groups, n = 4 miRNA-NC-treated groups. P, Q Representative images (P) and wound healing percentage (Q) of the endothelial cell line transfected with miR-188-3p or miRNA-NC in the wound healing assays. Scale bar = 500 μm. n = 3 in each group. R, S Representative images (R) and quantitative analysis (S) of the migrated cells from a Transwell migration assay. Scale bar = 500 μm. n = 4 miR-188-3p-treated group, n = 5 miRNA-NC-treated group. T, U The relative expression of Emcn (T) and CD31 (U) in the HMEC-1 cells transfected with miR-188-3p mimics or miRNA-NC. n = 3 in each group. NC: treated with miRNA-NC, miR-188-3p mimics: treated with miR-188-3p mimics. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by two-tailed Student’s t test or Welch’s t test.CC BY · PubMed Central
Fig. 3 Mice with endothelial cell-specific miR-188-3p overexpression showed reduced type H vessels and bone mass. A Representative images of Emcn (red) and GFP (green) immunostaining. Scale bar = 50 μm. B Representative images of Emcn (red) and CD31 (green) immunostaining of femur sections from the indicated groups. Scale bar = 75 μm. C Quantification of the type H vessels in femur sections. n = 3 in each group. D–H Representative microcomputed tomography (μCT) images (D) and quantitative μCT analysis (E–H) of trabecular bone microarchitecture in femora from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. n = 10 mice with endothelial cell-specific miRNA-NC overexpression, n = 14 mice with endothelial cell-specific miR-188-3p overexpression. I Representative images of haematoxylin-eosin staining in femora of the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 500 μm. J, K Representative images (J) and quantitative analysis (K) of osteocalcin immunohistochemical staining from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 50 μm. n = 4 in each group. L, M Representative images (L) and quantitative analysis (M) of TRAP staining from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 4 in each group. TIE-NC OE overexpression of miRNA-NC in endothelial cells, TIE-3P OE overexpression of miR-188-3p in endothelial cells. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.001 by two-tailed Student’s t test.
Fig. 3 Mice with endothelial cell-specific miR-188-3p overexpression showed reduced type H vessels and bone mass. A Representative images of Emcn (red) and GFP (green) immunostaining. Scale bar = 50 μm. B Representative images of Emcn (red) and CD31 (green) immunostaining of femur sections from the indicated groups. Scale bar = 75 μm. C Quantification of the type H vessels in femur sections. n = 3 in each group. D–H Representative microcomputed tomography (μCT) images (D) and quantitative μCT analysis (E–H) of trabecular bone microarchitecture in femora from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. n = 10 mice with endothelial cell-specific miRNA-NC overexpression, n = 14 mice with endothelial cell-specific miR-188-3p overexpression. I Representative images of haematoxylin-eosin staining in femora of the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 500 μm. J, K Representative images (J) and quantitative analysis (K) of osteocalcin immunohistochemical staining from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 50 μm. n = 4 in each group. L, M Representative images (L) and quantitative analysis (M) of TRAP staining from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 4 in each group. TIE-NC OE overexpression of miRNA-NC in endothelial cells, TIE-3P OE overexpression of miR-188-3p in endothelial cells. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.001 by two-tailed Student’s t test.CC BY · PubMed Central
Fig. 4 Mice with endothelial cell-specific miR-188-3p overexpression showed reduced type H vessels and delayed bone regeneration during bone damage repair. A Representative μCT images of trabecular bone microarchitecture in the bone regeneration area from 3-month-old and 12-month-old mice 0 days and 7 days after surgery. B–E Quantification of the trabecular bone microarchitecture in the femora of the bone generation area from 3-month-old and 12-month-old mice. n = 9 (3-month-old mice), n = 10 (12-month-old mice). F, G Representative images (F) and quantitative analysis (G) of Emcn (red) and CD31 (green) immunostaining of the bone regeneration area in femur sections from the indicated mice. Scale bar = 100 μm. n = 3 in each group. H, I Representative images (H) and quantitative analysis (I) of Emcn (red) and CD31 (green) immunostaining of the bone regeneration area in femur sections from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 5 mice with endothelial cell-specific miRNA-NC overexpression, n = 3 mice with endothelial cell-specific miR-188-3p overexpression. J–N Representative μCT images (J) and quantification (K–N) of trabecular bone microarchitecture in the bone generation area from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. n = 10 mice with endothelial cell-specific miRNA-NC overexpression, n = 11 mice with endothelial cell-specific miR-188-3p overexpression. O Representative images of haematoxylin-eosin staining in the bone generation area of the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 500 μm. P, Q Representative images (P) and quantitative analysis (Q) of osteocalcin immunohistochemical staining in the bone generation area from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 4 in each group. R, S Representative images (R) and quantitative analysis (S) of TRAP staining in the bone generation area from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 4 in each group. TIE-NC OE overexpression of miRNA-NC in endothelial cells, TIE-3P OE overexpression of miR-188-3p in endothelial cells. BRA bone regeneration, mo month. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by one-way ANOVA in (G), and two-tailed Student’s t test or Welch’s t test in the rest panels.
Fig. 4 Mice with endothelial cell-specific miR-188-3p overexpression showed reduced type H vessels and delayed bone regeneration during bone damage repair. A Representative μCT images of trabecular bone microarchitecture in the bone regeneration area from 3-month-old and 12-month-old mice 0 days and 7 days after surgery. B–E Quantification of the trabecular bone microarchitecture in the femora of the bone generation area from 3-month-old and 12-month-old mice. n = 9 (3-month-old mice), n = 10 (12-month-old mice). F, G Representative images (F) and quantitative analysis (G) of Emcn (red) and CD31 (green) immunostaining of the bone regeneration area in femur sections from the indicated mice. Scale bar = 100 μm. n = 3 in each group. H, I Representative images (H) and quantitative analysis (I) of Emcn (red) and CD31 (green) immunostaining of the bone regeneration area in femur sections from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 5 mice with endothelial cell-specific miRNA-NC overexpression, n = 3 mice with endothelial cell-specific miR-188-3p overexpression. J–N Representative μCT images (J) and quantification (K–N) of trabecular bone microarchitecture in the bone generation area from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. n = 10 mice with endothelial cell-specific miRNA-NC overexpression, n = 11 mice with endothelial cell-specific miR-188-3p overexpression. O Representative images of haematoxylin-eosin staining in the bone generation area of the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 500 μm. P, Q Representative images (P) and quantitative analysis (Q) of osteocalcin immunohistochemical staining in the bone generation area from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 4 in each group. R, S Representative images (R) and quantitative analysis (S) of TRAP staining in the bone generation area from the 3-month-old mice with endothelial cell-specific miR-188-3p or miRNA-NC overexpression. Scale bar = 100 μm. n = 4 in each group. TIE-NC OE overexpression of miRNA-NC in endothelial cells, TIE-3P OE overexpression of miR-188-3p in endothelial cells. BRA bone regeneration, mo month. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by one-way ANOVA in (G), and two-tailed Student’s t test or Welch’s t test in the rest panels.CC BY · PubMed Central
Fig. 5 Mice with knockout miR-188 showed more type H vessels and accelerated bone regeneration during bone damage repair. A Representative images of Emcn (red) and CD31 (green) immunostaining of the bone regeneration area in femur sections from the indicated mice. Scale bar = 100 μm. B Quantitative analysis of type H vessels in the bone regeneration area of femora from the indicated mice. n = 3 (3-month-old WT or miR188−/− mice), n = 4 (6-month-old and 15-month-old WT or miR188−/− mice). C Representative μCT images of trabecular bone microarchitecture in the bone regeneration area from 3-month-, 6-month-, and 15-month-old WT or miR188−/− mice 0 days and 7 days after surgery. D–G Quantitative analysis of trabecular bone microarchitecture in the bone generation area from the indicated mice. n = 4 (3-month WT mice), n = 6 (3-month miR188−/− mice and 6-month WT mice), n = 5 (6-month miR188−/− mice), n = 10 (15-month WT mice), n = 8 (15-month miR188−/− mice). BRA: bone regeneration; mo: month. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by two-tailed Student’s t test.
Fig. 5 Mice with knockout miR-188 showed more type H vessels and accelerated bone regeneration during bone damage repair. A Representative images of Emcn (red) and CD31 (green) immunostaining of the bone regeneration area in femur sections from the indicated mice. Scale bar = 100 μm. B Quantitative analysis of type H vessels in the bone regeneration area of femora from the indicated mice. n = 3 (3-month-old WT or miR188−/− mice), n = 4 (6-month-old and 15-month-old WT or miR188−/− mice). C Representative μCT images of trabecular bone microarchitecture in the bone regeneration area from 3-month-, 6-month-, and 15-month-old WT or miR188−/− mice 0 days and 7 days after surgery. D–G Quantitative analysis of trabecular bone microarchitecture in the bone generation area from the indicated mice. n = 4 (3-month WT mice), n = 6 (3-month miR188−/− mice and 6-month WT mice), n = 5 (6-month miR188−/− mice), n = 10 (15-month WT mice), n = 8 (15-month miR188−/− mice). BRA: bone regeneration; mo: month. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by two-tailed Student’s t test.CC BY · PubMed Central
Fig. 6 miR-188-3p inhibited angiogenesis by targeting ITGβ3. A, B Western blotting analysis of the potential and angiogenesis-related targets of miR-188-3p expression in the HMEC-1 cells transfected with miR-188-3p mimics or miRNA-NC. n = 3 in each group. C Schematic of miR-188 targeting the 3′UTR of ITGβ3 mRNA. D The luciferase activity of luciferase reporter plasmids containing ITGβ3-WT 3′UTR and ITGβ3-MUT 3′UTR cotransfected with miR-188-3p mimics or miRNA-NC in HMEC-1 cells. n = 3 in each group. E, F Representative images of Western blotting (E) and quantitative analysis of ITGβ3 protein expression levels (F) in the HMEC-1 cells transfected with ITGβ3-siRNA or siRNA-NC. n = 3 in each group. G Quantitative analysis of ITGβ3 mRNA expression levels in the HMEC-1 cells transfected with ITGβ3-siRNA or siRNA-NC. n = 4 in each group. H–J Representative images (H) and quantification (I, J) of tube junction numbers and total master segments length of tube formation assay from the indicated groups. Scale bar = 400 μm. n = 3 in each group. K, L Representative images (K) and wound healing percentage (L) of the HMECs transfected with ITGβ3-siRNA or siRNA-NC in the wound healing assays. Scale bar = 500 μm. n = 3 in each group. M, N Representative images (M) and quantification (N) of migrated cells from a Transwell migration assay. Scale bar = 200 μm. n = 3 in each group. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by two-tailed Student’s t test.
Fig. 6 miR-188-3p inhibited angiogenesis by targeting ITGβ3. A, B Western blotting analysis of the potential and angiogenesis-related targets of miR-188-3p expression in the HMEC-1 cells transfected with miR-188-3p mimics or miRNA-NC. n = 3 in each group. C Schematic of miR-188 targeting the 3′UTR of ITGβ3 mRNA. D The luciferase activity of luciferase reporter plasmids containing ITGβ3-WT 3′UTR and ITGβ3-MUT 3′UTR cotransfected with miR-188-3p mimics or miRNA-NC in HMEC-1 cells. n = 3 in each group. E, F Representative images of Western blotting (E) and quantitative analysis of ITGβ3 protein expression levels (F) in the HMEC-1 cells transfected with ITGβ3-siRNA or siRNA-NC. n = 3 in each group. G Quantitative analysis of ITGβ3 mRNA expression levels in the HMEC-1 cells transfected with ITGβ3-siRNA or siRNA-NC. n = 4 in each group. H–J Representative images (H) and quantification (I, J) of tube junction numbers and total master segments length of tube formation assay from the indicated groups. Scale bar = 400 μm. n = 3 in each group. K, L Representative images (K) and wound healing percentage (L) of the HMECs transfected with ITGβ3-siRNA or siRNA-NC in the wound healing assays. Scale bar = 500 μm. n = 3 in each group. M, N Representative images (M) and quantification (N) of migrated cells from a Transwell migration assay. Scale bar = 200 μm. n = 3 in each group. Data are shown as the mean ± SD. n.s. no significance; *P < 0.05; **P < 0.01; ***P < 0.001 by two-tailed Student’s t test.CC BY · PubMed Central

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Sorted by citations

Metadata

Authors
He, W.-Z., Yang, M., Jiang, Y., He, C., Sun, Y.-C., Liu, L., Huang, M., Jiao, Y.-R., Chen, K.-X., Hou, J., Huang, M., Xu, Y.-L., Feng, X., Liu, Y., Guo, Q., Peng, H., Huang, Y., Su, T., Xiao, Y., Li, Y., Zeng, C., Lei, G., Luo, X.-H., & Li, C.-J.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2022-05-25
Volume
13
Issue
5
ISSN
2041-4889
DOI
10.1038/s41419-022-04902-w
PMC
PMC9130327
Cited by
30
References
3
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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