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DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age
Ha-Neui Kim1,2, Jianhui Chang3, Lijian Shao3
1Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Abstract:
Age-related bone loss in mice results from a decrease in bone formation and an increase in cortical bone resorption. The former is accounted by a decrease in the number of postmitotic osteoblasts which synthesize the bone matrix and is thought to be the consequence of age-dependent changes in mesenchymal osteoblast progenitors. However, there are no specific markers for these progenitors, and conclusions rely on results from in vitro cultures of mixed cell populations. Moreover, the culprits of such changes remain unknown. Here, we have used Osx1-Cre;TdRFP mice in which osteoprogenitors express the TdRFP fluorescent protein. We report that the number of TdRFP-Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP-Osx1 cells from old mice exhibited markers of DNA damage and senescence, such as γH2AX foci, G1 cell cycle arrest, phosphorylation of p53, increased p21CIP1 levels, as well as increased levels of GATA4 and activation of NF-κB - two major stimulators of the senescence-associated secretory phenotype (SASP). Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro-osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.
Insights
Aging bone loss stems from fewer bone-building cells and more bone breakdown. This study identifies age-related DNA damage and senescence in osteoprogenitors, driving bone loss. Senolytic drugs show promise in reversing these effects.
Area of Science:
- Gerontology
- Cell Biology
- Bone Biology
Background:
- Age-related bone loss involves reduced bone formation and increased resorption.
- Osteoblast decline is linked to aging mesenchymal osteoblast progenitors, but their specific markers and causes are unknown.
- Current research relies on in vitro cultures of mixed cell populations, limiting understanding of progenitor cell changes.
Purpose of the Study:
- To identify specific markers for mesenchymal osteoblast progenitors.
- To investigate age-dependent changes in osteoprogenitor cells.
- To explore the role of senescence and DNA damage in age-related bone loss.
Main Methods:
- Utilized Osx1-Cre;TdRFP mice to fluorescently label osteoprogenitors.
- Quantified TdRFP-Osx1 cells in bone marrow from young (6 months) and old (24 months) mice.
- Assessed markers of DNA damage, senescence (γH2AX, p53, p21CIP1), GATA4, NF-κB activation, and SASP gene expression.
Main Results:
- Osteoprogenitor cell numbers (TdRFP-Osx1) decreased by over 50% in old mice.
- Old osteoprogenitors showed DNA damage and senescence markers, including G1 arrest and increased p53/p21CIP1.
- Old bone marrow stromal cells exhibited elevated SASP gene expression and supported increased osteoclast formation.
- Senolytic drug ABT263 significantly attenuated these age-related changes.
Conclusions:
- Intrinsic defects, including DNA damage and senescence, in osteoprogenitor cells contribute to age-related bone loss.
- These cellular changes lead to reduced osteoblast numbers and enhanced osteoclastogenesis.
- Targeting senescent osteoprogenitors with senolytic drugs may offer a therapeutic strategy for age-related bone diseases.