Date Published: February 28, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Bo Gao, Xisheng Lin, Huan Jing, Jing Fan, Chenchen Ji, Qiang Jie, Chao Zheng, Di Wang, Xiaolong Xu, Yaqian Hu, Weiguang Lu, Zhuojing Luo, Liu Yang.
Aging drives the accumulation of senescent cells (SnCs) including stem/progenitor cells in bone marrow, which contributes to aging‐related bone degenerative pathologies. Local elimination of SnCs has been shown as potential treatment for degenerative diseases. As LepR+ mesenchymal stem/progenitor cells (MSPCs) in bone marrow are the major population for forming bone/cartilage and maintaining HSCs niche, whether local elimination of senescent LepR+MSPCs delays aging‐related pathologies and improves local microenvironment need to be well defined. In this study, we performed local delivery of tetramethylpyrazine (TMP) in bone marrow of aging mice, which previously showed to be used for the prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP). We found the increased accumulation of senescent LepR+MSPCs in bone marrow of aging mice, and TMP significantly inhibited the cell senescent phenotype via modulating Ezh2‐H3k27me3. Most importantly, local delivery of TMP improved bone marrow microenvironment and maintained bone homeostasis in aging mice by increasing metabolic and anti‐inflammatory responses, inducing H‐type vessel formation, and maintaining HSCs niche. These findings provide evidence on the mechanisms, characteristics and functions of local elimination of SnCs in bone marrow, as well as the use of TMP as a potential treatment to ameliorate human age‐related skeletal diseases and to promote healthy lifespan.
Aging is the main causative pathological factor for bone degenerative diseases and functional deficits in humans (Finch, 2010; Stenderup, Justesen, Clausen, & Kassem, 2003). During aging, bone homeostasis is interrupted with the chaos of the marrow microenvironment, including a disrupted HSC niche (Mendelson & Frenette, 2014), decreased vessel formation (Kusumbe, Ramasamy, & Adams, 2014) and abnormal inflammation factor release (Lepperdinger, 2011). As a result, increased cellular senescence in bone marrow can be induced by cellular damage or environment changes. It is reported that senescent cells (SnCs) accumulate in bone marrow with aging (Farr et al., 2017) and contribute to age‐related pathologies through their secretion of factors contributing to the senescence‐associated secretory phenotype (SASP) (Campisi, 2000, 2013; Nelson et al., 2012). SnCs exhibit essentially stable cell cycle arrest through the actions of tumour suppressors such as p16INK4a, p53, p21CIP1 (Campisi, 2005; Serrano, Lin, McCurrach, Beach, & Lowe, 1997) and also include increased lysosomal β‐galactosidase activity, robust secretion of inflammatory cytokines/chemokines, and nuclear foci containing DNA damage response proteins or distinctive heterochromatin. Although cell senescence has been well studied in recent decades, the mechanisms and local treatment targets for SnCs‐induced bone degenerative disease are not well understood.
Senescent cell (SnC) accumulation in bone marrow with aging leads to aging‐related pathologies, and local ablation of SnCs attenuates several pathologic processes and extends a healthy lifespan (Finch, 2010; Jeon et al., 2017). There have been great efforts in understanding the mechanism of aging‐induced SnCs in bone marrow and the underlying potential treatment. In this study, we found that senescent LepR+ MSPCs accumulated in the bone marrow of aging mice with bone degeneration and that local delivery of TMP in bone marrow inhibited LepR+ MSPC senescence, which is essentially and epigenetically controlled by Ezh2‐H3K27me3. Moreover, TMP maintained the HSC niche and created an anti‐inflammatory and angiogenic environment in the bone marrow of aging mice.
L.Y. and B.G. designed the experiments; B.G., X.S.L. and H.J. carried out most of the experiments; J.F., Q.J., C.C.J, X.L.X, D. W, W.G.L. and Y.Q.H. helped to collect the samples. C.Z. proofread the manuscript; L.Y. and Z.J.L supervised the experiments, analysed results and wrote the manuscript.
No competing financial interests exist. No benefits in any form have been or will be received from a commercial party directly or indirectly by the authors of this article.