Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing

Abstract Mesenchymal stem cells (MSCs) undergo osteogenic differentiation during bone defect healing. However, the role of JAK2/STAT3 in the osteogenic differentiation of MSCs and bone defect healing is still not fully understood. In this study, we aimed to analyze the effect of AG490, a JAK2-specific inhibitor, on MSCs proliferation and osteogenic differentiation as well as in bone defect healing. We used AG490 to inhibit the JAK2/STAT3 signaling in a mice bone marrow stromal cells (BMSCs) culture. AG490 inhibited BMSCs proliferation and osteogenic differentiation markers, i.e. Col1α, Alp and Ocn expression in mRNA and protein levels. Inhibition of JAK2 reduced ALP activity and matrix mineralization in BMSCs culture. Inhibition of JAK2 reduced phosphorylation of STAT3, AKT, P38, and JNK phosphorylation. Immunohistochemistry showed high numbers of pJAK2, pSTAT3 and ALP positive cells and AG490 reduced this effect in vivo. Histology and μ-computed tomography (CT) data showed that AG490 treatment inhibits bone regeneration and bone defect healing. Our results clearly showed the inhibitory effect of AG490 on proliferation and osteogenic differentiation of BMSCs, bone regeneration and bone defect healing. Moreover, AG490 inhibited phosphorylation of STAT3, P38, JNK and AKT. This suggests the possible role of JAK2/STAT3 signaling in hypoxia-induced osteogenic differentiation of MSCs and bone defect healing.

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Periodontal ligament‑associated protein‑1 delays rat periodontal bone defect repair by regulating osteogenic differentiation of bone marrow stromal cells and osteoclast activation

International Journal of Molecular Medicine ◽

10.3892/ijmm.2017.3312 ◽

2017 ◽

Cited By ~ 2

Author(s):

Xijiao Yu ◽

Shuang Liu ◽

Wei Wang ◽

Shu Li

Keyword(s):

Bone Marrow ◽

Osteogenic Differentiation ◽

Bone Defect ◽

Stromal Cells ◽

Periodontal Ligament ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Bone Defect Repair ◽

Defect Repair ◽

Osteoclast Activation

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Role of ecto-NTPDases on UDP-sensitive P2Y6receptor activation during osteogenic differentiation of primary bone marrow stromal cells from postmenopausal women

Journal of Cellular Physiology ◽

10.1002/jcp.23014 ◽

2012 ◽

Vol 227 (6) ◽

pp. 2694-2709 ◽

Cited By ~ 31

Author(s):

J.B. Noronha-Matos ◽

M.A. Costa ◽

M.T. Magalhães-Cardoso ◽

F. Ferreirinha ◽

J. Pelletier ◽

...

Keyword(s):

Bone Marrow ◽

Osteogenic Differentiation ◽

Postmenopausal Women ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Primary Bone ◽

Primary Bone Marrow

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The role of lithium in the osteogenic bioactivity of clay nanoparticles

Biomaterials Science ◽

10.1039/d0bm01444c ◽

2021 ◽

Author(s):

Mohamed Abdelsattar Mohamed Mousa ◽

Oscar Kelly ◽

Jane Doyle ◽

Nicholas D Evans ◽

Richard O Oreffo ◽

...

Keyword(s):

Bone Marrow ◽

Osteogenic Differentiation ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Clay Nanoparticles

LAPONITETM (herein Laponite) clay nanoparticles are known to promote osteogenic differentiation of human bone marrow stromal cells (HBMSCs), but the specific properties of Laponite that impart its osteogenic bioactivity are...

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A dual role of cholesterol in osteogenic differentiation of bone marrow stromal cells

Journal of Cellular Physiology ◽

10.1002/jcp.27635 ◽

2018 ◽

Vol 234 (3) ◽

pp. 2058-2066 ◽

Cited By ~ 5

Author(s):

Kun Li ◽

Chunmei Xiu ◽

Qiang Zhou ◽

Li Ni ◽

Jun Du ◽

...

Keyword(s):

Bone Marrow ◽

Osteogenic Differentiation ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Dual Role ◽

Marrow Stromal Cells

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Cellular hypoxia promotes osteogenic differentiation of mesenchymal stem cells and bone defect healing via STAT3 signaling

Cellular & Molecular Biology Letters ◽

10.1186/s11658-019-0191-8 ◽

2019 ◽

Vol 24 (1) ◽

Cited By ~ 8

Author(s):

Xin Yu ◽

Qilong Wan ◽

Xiaoling Ye ◽

Yuet Cheng ◽

Janak L. Pathak ◽

...

Keyword(s):

Osteogenic Differentiation ◽

Bone Defect ◽

Precursor Cells ◽

Defect Healing ◽

Stat3 Signaling ◽

Bone Defect Healing ◽

Cellular Hypoxia

Abstract Background Hypoxia in the vicinity of bone defects triggers the osteogenic differentiation of precursor cells and promotes healing. The activation of STAT3 signaling in mesenchymal stem cells (MSCs) has similarly been reported to mediate bone regeneration. However, the interaction between hypoxia and STAT3 signaling in the osteogenic differentiation of precursor cells during bone defect healing is still unknown. Methods In this study, we assessed the impact of different durations of CoCl2-induced cellular hypoxia on the osteogenic differentiation of MSCs. Role of STAT3 signaling on hypoxia induced osteogenic differentiation was analyzed both in vitro and in vivo. The interaction between cellular hypoxia and STAT3 signaling in vivo was investigated in a mouse femoral bone defect model. Results The peak osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) occurred after 3 days of hypoxia. Inhibiting STAT3 reversed this effect. Hypoxia enhanced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and STAT3 phosphorylation in MSCs. Histology and μ-CT results showed that CoCl2 treatment enhanced bone defect healing. Inhibiting STAT3 reduced this effect. Immunohistochemistry results showed that CoCl2 treatment enhanced Hif-1α, ALP and pSTAT3 expression in cells present in the bone defect area and that inhibiting STAT3 reduced this effect. Conclusions The in vitro study revealed that the duration of hypoxia is crucial for osteogenic differentiation of precursor cells. The results from both the in vitro and in vivo studies show the role of STAT3 signaling in hypoxia-induced osteogenic differentiation of precursor cells and bone defect healing.

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Activation of 4-1BB signaling in bone marrow stromal cells triggers bone loss via the p-38 MAPK-DKK1 axis in aged mice

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00605-y ◽

2021 ◽

Author(s):

Daqian Wan ◽

Songtao Ai ◽

Huoniu Ouyang ◽

Liming Cheng

Keyword(s):

Bone Marrow ◽

Bone Loss ◽

Osteogenic Differentiation ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Bone Marrow Microenvironment ◽

Marrow Stromal Cells ◽

Senile Osteoporosis ◽

Aged Mice ◽

Old Mice

AbstractSenile osteoporosis can cause bone fragility and increased fracture risks and has been one of the most prevalent and severe diseases affecting the elderly population. Bone formation depends on the proper osteogenic differentiation of bone marrow stromal cells (BMSCs) in the bone marrow microenvironment, which is generated by the functional relationship among different cell types in the bone marrow. With aging, bone marrow provides signals that repress osteogenesis. Finding the signals that oppose BMSC osteogenic differentiation from the bone marrow microenvironment and identifying the abnormal changes in BMSCs with aging are key to elucidating the mechanisms of senile osteoporosis. In a pilot experiment, we found that 4-1BBL and 4-1BB were more abundant in bone marrow from aged (18-month-old) mice than young (6-month-old) mice. Meanwhile, significant bone loss was observed in aged mice compared with young mice. However, very little data have been generated regarding whether high-level 4-1BB/4-1BBL in bone marrow was associated with bone loss in aged mice. In the current study, we found upregulation of 4-1BB in the BMSCs of aged mice, which resulted in the attenuation of the osteogenic differentiation potential of BMSCs from aged mice via the p38 MAPK-Dkk1 pathway. More importantly, bone loss of aged mice could be rescued through the blockade of 4-1BB signaling in vivo. Our study will benefit not only our understanding of the pathogenesis of age-related trabecular bone loss but also the search for new targets to treat senile osteoporosis.

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