title: DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age.
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 p21CIP1levels, 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.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Ha-Neui
authors.initials: HN
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Srividhya
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D000814:Aniline Compounds; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050991:GATA4 Transcription Factor; D006657:Histones; D008164:Luminescent Proteins; D016328:NF-kappa B; D000076182:Sp7 Transcription Factor; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D000097573:Red Fluorescent Protein; C493957:Cdkn1a protein, mouse; C484171:Gata4 protein, mouse; C479466:Sp7 protein, mouse; C475961:gamma-H2AX protein, mouse; C528561:navitoclax
keywords: ABT263; GATA4; NF-κB; osteoblasts; osteoporosis; p21; p53