JAK2/STAT3 regulates estrogen-related senescence of bone marrow stem cells

in Journal of Endocrinology
Authors:
Wenjing Wu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Jiayao Fu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Yijing Gu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Yu Wei Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Pengfei Ma Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Junhua Wu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Correspondence should be addressed to J Wu: wujunhua_sh@tongji.edu.cn
DOI:
https://doi.org/10.1530/JOE-19-0518
Volume/Issue:
Volume 245: Issue 1
Article Type:
Research Article
Page Range:
141–153
Online Publication Date:
Apr 2020
Copyright:
© 2020 Society for Endocrinology 2020
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Emerging evidence has indicated that estrogen deficiency contributes to osteoporosis by affecting the level of inflammation. The inflammation microenvironment affects many cellular physiological processes, one of which may be cellular senescence according to previous studies. Senescent cells cannot function normally and secrete inflammatory cytokines and degradative proteins, which are referred to as senescence-associated secretory phenotype (SASP) factors, inducing further senescence and inflammation. Thus, stopping this vicious cycle may be helpful for postmenopausal osteoporosis treatment. Here, we used ovariectomized (OVX) mice as an estrogen-deficient model and confirmed that OVX bone marrow mesenchymal stem cells (BMSCs) displayed a senescent phenotype and upregulated SASP factor secretion both in vitro and in vivo. Furthermore, JAK2/STAT3, an important cytokine secretion-related signalling pathway that is associated with SASP secretion, was activated. Estrogen addition and estrogen receptor blockade confirmed that the JAK2/STAT3 axis participated in OVX BMSC senescence by mediating SASP factors. And JAK inhibition reduced SASP factor expression, alleviated senescence and enhanced osteogenic differentiation. Intraperitoneal injection of a JAK inhibitor, ruxolitinib, prevented bone loss in OVX mice. Collectively, our results revealed that JAK2/STAT3 plays an important role in the inflammation-senescence-SASP feedback loop in OVX BMSCs and that JAK inhibition could be a new method for treating postmenopausal osteoporosis.

Supplementary Materials

    • Supplementary Figure 1 The uterus morphologies and weights in sham-operated (Sham) and OVX mice. *p < 0.05, n=5 (t-test).
    • Supplementary Figure 2 Identification of isolated BMSCs. (A) Flow cytometry analysis of cells. (B) Representative image of the colony formation assay stained with crystal violet solution. (C) Alizarin Red staining after 21 days of osteogenic induction. (D) Oil Red O staining after 16 days of adipogenic induction. Scale bar: 100 &#x03BC;m. (E) Alcian blue staining after 18 days of chondrogenic induction. Scale bar: 100 &#x03BC;m.
    • Supplementary Figure 3 OVX BMSCs exhibit enhanced senescence and JAK2/STAT3 pathway activation. (A) qPCR detection of the senescence biomarkers, p53 and p21, in Sham and OVX BMSCs. (B) Western blot detection of P53 and P21 in Sham and OVX BMSCs. (C) Representative images and quantification of SA-&#x03B2;-gal-positive cells in Sham and OVX BMSCs stained with DAPI (dark cytoplasmic blue: SA-&#x03B2;-gal; light blue: DAPI). Scale bar: 50 &#x03BC;m. (D) Representative images and quantification of KI67-positive cells in Sham and OVX BMSCs stained with DAPI (green: KI67; blue: DAPI). Scale bar: 50 &#x03BC;m. (E) Expression of osteogenic genes (Alp, Runx2, and Ocn) after 7 days of osteogenic induction in each group. (F) Alizarin Red staining after 21 days of osteogenic induction in each group. (G) qPCR detection of SASP factors in Sham and OVX BMSCs. (H) Total and phosphorylated JAK2/STAT3 protein expression in each group. *p < 0.05, n=3 (Chi-square test for frequency of SA-&#x03B2;-gal- and KI67-positive cells in each group; t-test for other comparisons with OVX group).
    • Supplementary Figure 4 Western blot detection of PSTAT3 and STAT3 in bone tissue after JAKi injection.
    • Supplementary Figure 5 Body weights of mice after operation and treatment. *p < 0.05, n=5 (t-test for the comparisons with OVX group).
    • Supplementary Figure 6 Micro-CT reconstruction images and bone parameter analysis of the fifth lumbar spinal vertebra(LV5). Scale bar: 1 mm. *p < 0.05, n=5 (t-test for the comparisons with OVX group).
    • Supplementary Figure 7 Representative Trap staining images and quantity of each group. Scale bar: 100 &#x03BC;m. *p < 0.05, n=3 (t-test for the comparisons with OVX group).
    • Supplementary Table 1 Primer sequence of the genes used in this study.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
13
Article Type:
Research Article
Received Date:
19 Jan 2020
Accepted Date:
10 Feb 2020
Print Publication Date:
01 Apr 2020
Online Publication Date:
Apr 2020
Keywords:
cellular senescence; JAK2/STAT3; BMSCs; SASP; postmenopausal osteoporosis