Bone Marrow Adiposity in Models of Radiation- and Aging-Related Bone Loss Is Dependent on Cellular Senescence.
Abhishek ChandraAnthony B LagnadoJoshua N FarrMegan SchleusnerDavid G MonroeDominik SaulJoão F PassosSundeep KhoslaRobert J PignoloPublished in: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2022)
Oxidative stress-induced reactive oxygen species, DNA damage, apoptosis, and cellular senescence have been associated with reduced osteoprogenitors in a reciprocal fashion to bone marrow adipocyte tissue (BMAT); however, a direct (causal) link between cellular senescence and BMAT is still elusive. Accumulation of senescent cells occur in naturally aged and in focally radiated bone tissue, but despite amelioration of age- and radiation-associated bone loss after senescent cell clearance, molecular events that precede BMAT accrual are largely unknown. Here we show by RNA-Sequencing data that BMAT-related genes were the most upregulated gene subset in radiated bones of C57BL/6 mice. Using focal radiation as a model to understand age-associated changes in bone, we performed a longitudinal assessment of cellular senescence and BMAT. Using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA in situ hybridization of p21 transcripts and histological assessment of telomere dysfunction as a marker of senescence, we observed an increase in senescent cell burden of bone cells from day 1 postradiation, without the presence of BMAT. BMAT was significantly elevated in radiated bones at day 7, confirming the qRT-PCR data in which most BMAT-related genes were elevated by day 7, and the trend continued until day 42 postradiation. Similarly, elevation in BMAT-related genes was observed in bones of aged mice. The senolytic cocktail of Dasatinib (D) plus Quercetin (Q) (ie, D + Q), which clears senescent cells, reduced BMAT in aged and radiated bones. MicroRNAs (miRNAs or miRs) linked with senescence marker p21 were downregulated in radiated and aged bones, whereas miR-27a, a miR that is associated with increased BMAT, was elevated both in radiated and aged bones. D + Q downregulated miR-27a in radiated bones at 42 days postradiation. Overall, our study provides evidence that BMAT occurrence in oxidatively stressed bone environments, such as radiation and aging, is induced following a common pathway and is dependent on the presence of senescent cells. © 2022 American Society for Bone and Mineral Research (ASBMR).
Keyphrases
- bone loss
- dna damage
- cell cycle arrest
- induced apoptosis
- bone marrow
- oxidative stress
- endothelial cells
- cell proliferation
- bone mineral density
- long non coding rna
- single cell
- endoplasmic reticulum stress
- stress induced
- reactive oxygen species
- dna repair
- cell death
- mesenchymal stem cells
- soft tissue
- long noncoding rna
- cell therapy
- bone regeneration
- radiation induced
- type diabetes
- signaling pathway
- high fat diet induced
- metabolic syndrome
- gene expression
- risk factors
- drug induced
- machine learning
- big data
- genome wide
- mass spectrometry
- physical activity
- nucleic acid