Abstract
SummaryAging 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.
Highlights
Aging is the main causative pathological factor for bone degenerative diseases and functional deficits in humans (Finch, 2010; Stenderup, Justesen, Clausen, & Kassem, 2003)
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)
We showed that TMP significantly decreased p16INK4a+ and senescenceassociated b-galactosidase (SA-bGal)+ cells and increased BrdU+ cells as previously shown, while knock-down of Ezh2 markedly blocked the antisenescence and proliferative effects of TMP (Figure 3j–l), which indicates the essential role of Ezh2 in modulating the TMP-induced antisenescence and proliferative effects on aging LepR+ mesenchymal stem/progenitor cells (MSPCs)
Summary
Aging is the main causative pathological factor for bone degenerative diseases and functional deficits in humans (Finch, 2010; Stenderup, Justesen, Clausen, & Kassem, 2003). As a result, increased cellular senescence in bone marrow can be induced by cellular damage or environment changes. 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 include increased lysosomal b-galactosidase activity, robust secretion of inflammatory cytokines/chemokines, and nuclear foci containing DNA damage response proteins or distinctive heterochromatin. 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
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