Serum CXCL2 Level Can Predict High-Fat Diet-Induced Impairment of Bone Marrow Mesenchymal Stem Cells

Abstract Background: Disorders of bone metabolism caused by hyperlipidemia is not conducive to osseointegration of implants. Autophagy, an evolutionarily conserved, lysosomal-mediated degradation process, is indispensable for bone homeostasis, its effects on hyperlipidemia-induced osteoporosis remain to be elucidated. The objective of this study was to determine whether autophagy affects bone metabolism and implant osseointegration through regulating the function of bone marrow mesenchymal stem cells (BMMSCs) in rats with hyperlipidemia and to confirm signaling pathway involved in the regulation of autophagy. Methods: Hyperlipidemia models were established through a long-term high-carbohydrate, high-fat diet in 6-week-old male Sprague-Dawley rats. The impact of hyperlipidemia on bone metabolism and early osseointegration of implants was explored by the methods including serum biochemical detection, micro-computed tomography and bone morphology detection. Biological properties and autophagy levels of BMMSCs were also determined. Further, we determined if autophagy was involved in bone metabolism changes resulting from high-fat diet by focusing on the lineage differentiation of BMMSCs. The signaling pathway involved in the regulation of autophagy was also explored.Results: The high-carbohydrate, high-fat diet (HCHF) was given to the rats for seven months aggravated bone loss in the cancellous bone and reduced osseointegration of implants. BMMSCs from hyperlipidemia rats exhibited decreased osteogenesis, increased adipogenesis and decreased autophagic activity compared with regular diet (RD) BMMSCs. Rapamycin treatment restored the impaired osteogenic differentiation and inhibited the adipogenic differentiation of HCHF-BMMSCs through the activation of autophagy. Further, AMPK/mTOR signaling pathways was related to the impairment of autophagy of HCHF-BMMSCs. Conclusions: Our data indicate that long-term high-carbohydrate, high-fat diet-induced hyperlipidemia hampers the differentiation balance of bone marrow mesenchymal stem cells by suppressing autophagy via the AMPK/ mTOR pathway, which ultimately led to aggravated bone loss in the cancellous bone and reduced osseointegration of implants in rat models.

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Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss

Frontiers in Endocrinology ◽

10.3389/fendo.2020.622950 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yujue Li ◽

Lingyun Lu ◽

Ying Xie ◽

Xiang Chen ◽

Li Tian ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Bone Loss ◽

Interleukin 6 ◽

High Fat Diet ◽

Cell Senescence ◽

Low Grade ◽

High Fat ◽

Bone Mesenchymal Stem Cells

Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

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CXCL2 Impairs Functions of Bone Marrow Mesenchymal Stem Cells and Can Serve as a Serum Marker in High-Fat Diet-Fed Rats

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.687942 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jianhai Bi ◽

Qiuchen Li ◽

Zhigang Yang ◽

Lei Cai ◽

Tao Lv ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Inflammatory Cytokines ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Serum Marker ◽

Cytokine Signaling ◽

Low Grade ◽

High Fat

In modern society excessive consumption of a high-fat diet (HFD) is a significant risk factor for many diseases such as diabetes, osteoarthritis and certain cancers. Resolving cellular and molecular mechanisms underlying HFD-associated disorders is of great importance to human health. Mesenchymal stem cells (MSCs) are key players in tissue homeostasis and adversely affected by prolonged HFD feeding. Low-grade systemic inflammation induced by HFD is characterized by increased levels of pro-inflammatory cytokines and alters homeostasis in many organs. However, whether, which and how HFD associated inflammatory cytokines impair MSCs remain unclear. Here we demonstrated that HFD induced serum cytokines disturbances, especially a continuous elevation of serum CXCL2 level in rats. Coincidentally, the differentially expressed genes (DEGs) of bone marrow MSCs (BMSCs) which functions were impaired in HFD rats were enriched in cytokine signaling. Further mechanism analysis revealed that CXCL2 treatment in vitro suppresses the adipogenic potential of BMSCs via Rac1 activation, and promoted BMSC migration and senescence by inducing over-production of ELMO1 and reactive oxygen species (ROS) respectively. Moreover, we found that although glycolipid metabolism indicators can be corrected, the CXCL2 elevation and BMSC dysfunctions cannot be fully rescued by diet correction and anti-inflammatory aspirin treatment, indicating the long-lasting deleterious effects of HFD on serum CXCL2 levels and BMSC functions. Altogether, our findings identify CXCL2 as an important regulator in BMSCs functions and may serve as a serum marker to indicate the BMSC dysfunctions induced by HFD. In addition, our findings underscore the intricate link among high-fat intake, chronic inflammation and BMSC dysfunction which may facilitate development of protective strategies for HFD associated diseases.

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Experimental Study on Sdccag3 Regulating Osteogenesis and Adipogenic Differentiation of Rats Bone Marrow Mesenchymal Stem Cells

10.21203/rs.3.rs-1059024/v1 ◽

2021 ◽

Author(s):

Mengqi Yuan ◽

Fenglei Huo ◽

Huiping Ren ◽

Qiushuang Guo ◽

Jing Lan

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Bone Formation ◽

Adipogenic Differentiation ◽

New Bone Formation ◽

Rt Pcr ◽

High Fat ◽

Marrow Mesenchymal Stem Cells ◽

Specific Pathway

Abstract Background Bone marrow mesenchymal stem cells have a metabolic balance between osteogenic and adipogenic differentiation. Sdccag3 is differentially expressed in hyperlipidemia rats, and it can be beneficial to the osteogenesis disorder caused by dyslipidemia, but the pathway mechanism and its influence on the differentiation have not been studied. Methods Here, we designed RT-PCR and Western Blot to determine the expression of Osteogenic and lipid gene, including ALP, Runx2, PPARγ FABP4 and so on, and then we performed microarray to evaluate the bone formation, calculate BV/TV. Simultaneously, we detected mRNA from the hyperlipidemia rat model we established to find the specific pathway mechanism. Results In this experiment, we found that high fat environment influences BMSCs differentiation. Sdccag3 overexpression upregulates the osteogenic differentiation of BMSCs and increased new bone formation. Conclusion Therefore, our findings show that Sdccag3 regulates osteogenesis and adipogenic differentiation of BMSCs.

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