{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T07:48:07Z","timestamp":1794124087756,"version":"4.8.0"},"reference-count":98,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20KK0356"],"award-info":[{"award-number":["20KK0356"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20KK0356"],"award-info":[{"award-number":["20KK0356"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21H03124"],"award-info":[{"award-number":["21H03124"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20KK0356"],"award-info":[{"award-number":["20KK0356"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20KK0356"],"award-info":[{"award-number":["20KK0356"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21H03124"],"award-info":[{"award-number":["21H03124"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The bone is an important organ that performs various functions, and the bone marrow inside the skeleton is composed of a complex intermix of hematopoietic, vascular, and skeletal cells. Current single-cell RNA sequencing (scRNA-seq) technology has revealed heterogeneity and sketchy differential hierarchy of skeletal cells. Skeletal stem and progenitor cells (SSPCs) are located upstream of the hierarchy and differentiate into chondrocytes, osteoblasts, osteocytes, and bone marrow adipocytes. In the bone marrow, multiple types of bone marrow stromal cells (BMSCs), which have the potential of SSPCs, are spatiotemporally located in distinct areas, and SSPCs\u2019 potential shift of BMSCs may occur with the advancement of age. These BMSCs contribute to bone regeneration and bone diseases, such as osteoporosis. In vivo lineage-tracing technologies show that various types of skeletal lineage cells concomitantly gather and contribute to bone regeneration. In contrast, these cells differentiate into adipocytes with aging, leading to senile osteoporosis. scRNA-seq analysis has revealed that alteration in the cell-type composition is a major cause of tissue aging. In this review, we discuss the cellular dynamics of skeletal cell populations in bone homeostasis, regeneration, and osteoporosis.<\/jats:p>","DOI":"10.3390\/ijms24129814","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T02:28:45Z","timestamp":1686104925000},"page":"9814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Single-Cell RNA-Sequencing Reveals the Skeletal Cellular Dynamics in Bone Repair and Osteoporosis"],"prefix":"10.3390","volume":"24","author":[{"given":"Sixun","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-8539","authenticated-orcid":false,"given":"Shinsuke","family":"Ohba","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan"},{"name":"Department of Tissue and Developmental Biology, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9577-3249","authenticated-orcid":false,"given":"Yuki","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41467-019-14076-3","article-title":"Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis","volume":"11","author":"Fu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.stem.2018.06.009","article-title":"PGC-1alpha Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ","volume":"23","author":"Yu","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1002\/ca.23917","article-title":"Bone regeneration: A message from clinical medicine and basic science","volume":"35","author":"Tsukagoshi","year":"2022","journal-title":"Clin. Anat."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Chandra, A., and Rajawat, J. (2021). Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073553"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nature13193","article-title":"The role of senescent cells in ageing","volume":"509","year":"2014","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.celrep.2013.03.028","article-title":"p21 both attenuates and drives senescence and aging in BubR1 progeroid mice","volume":"3","author":"Baker","year":"2013","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/nm.4385","article-title":"Targeting cellular senescence prevents age-related bone loss in mice","volume":"23","author":"Farr","year":"2017","journal-title":"Nat. Med."},{"key":"ref_8","first-page":"381","article-title":"Osteogenesis in transplants of bone marrow cells","volume":"16","author":"Friedenstein","year":"1966","journal-title":"J. Embryol. Exp. Morphol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2007.08.025","article-title":"Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment","volume":"131","author":"Sacchetti","year":"2007","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nature09262","article-title":"Mesenchymal and haematopoietic stem cells form a unique bone marrow niche","volume":"466","author":"Michurina","year":"2010","journal-title":"Nature"},{"key":"ref_11","first-page":"263","article-title":"Bone marrow osteogenic stem cells: In vitro cultivation and transplantation in diffusion chambers","volume":"20","author":"Friedenstein","year":"1987","journal-title":"Cell Tissue Kinet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage potential of adult human mesenchymal stem cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF00572894","article-title":"Confocal images of marrow stromal (Westen-Bainton) cells","volume":"100","author":"Bianco","year":"1993","journal-title":"Histochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.devcel.2014.03.013","article-title":"Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development","volume":"29","author":"Mizoguchi","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1038\/s41467-017-02171-2","article-title":"Gli1 identifies osteogenic progenitors for bone formation and fracture repair","volume":"8","author":"Shi","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7319","DOI":"10.1038\/s41467-022-34804-6","article-title":"The fate of early perichondrial cells in developing bones","volume":"13","author":"Matsushita","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.stem.2014.06.008","article-title":"Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow","volume":"15","author":"Zhou","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1101\/gad.311068.117","article-title":"Stem cell niche-specific Ebf3 maintains the bone marrow cavity","volume":"32","author":"Seike","year":"2018","journal-title":"Genes. Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41586-019-1104-8","article-title":"The bone marrow microenvironment at single-cell resolution","volume":"569","author":"Tikhonova","year":"2019","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1002\/jbmr.3802","article-title":"The Unmixing Problem: A Guide to Applying Single-Cell RNA Sequencing to Bone","volume":"34","author":"Greenblatt","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"a026898","DOI":"10.1101\/cshperspect.a026898","article-title":"Single-Cell Applications of Next-Generation Sequencing","volume":"9","author":"Anaparthy","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1002\/stem.3336","article-title":"Potential applications of deep learning in single-cell RNA sequencing analysis for cell therapy and regenerative medicine","volume":"39","author":"Yan","year":"2021","journal-title":"Stem Cells"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1126\/science.161.3836.54","article-title":"Transplantation of marrow to extramedullary sites","volume":"161","author":"Tavassoli","year":"1968","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.cell.2014.12.002","article-title":"Identification and specification of the mouse skeletal stem cell","volume":"160","author":"Chan","year":"2015","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1084\/jem.20091046","article-title":"Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow","volume":"206","author":"Morikawa","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.stem.2018.01.008","article-title":"In Vivo Labeling by CD73 Marks Multipotent Stromal Cells and Highlights Endothelial Heterogeneity in the Bone Marrow Niche","volume":"22","author":"Breitbach","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41586-018-0662-5","article-title":"Resting zone of the growth plate houses a unique class of skeletal stem cells","volume":"563","author":"Mizuhashi","year":"2018","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41586-018-0554-8","article-title":"Discovery of a periosteal stem cell mediating intramembranous bone formation","volume":"562","author":"Debnath","year":"2018","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-023-38034-2","article-title":"Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis","volume":"14","author":"Matsushita","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1177\/10454411990100020401","article-title":"Bone marrow stromal cells: Characterization and clinical application","volume":"10","author":"Krebsbach","year":"1999","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.stem.2015.02.019","article-title":"Mesenchymal cell contributions to the stem cell niche","volume":"16","author":"Kfoury","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4649","DOI":"10.4049\/jimmunol.170.9.4649","article-title":"A role of CXC chemokine ligand 12\/stromal cell-derived factor-1\/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo","volume":"170","author":"Ara","year":"2003","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nature11926","article-title":"CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance","volume":"495","author":"Greenbaum","year":"2013","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41467-019-14029-w","article-title":"A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration","volume":"11","author":"Matsushita","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature10783","article-title":"Endothelial and perivascular cells maintain haematopoietic stem cells","volume":"481","author":"Ding","year":"2012","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S1074-7613(03)00201-2","article-title":"Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny","volume":"19","author":"Ara","year":"2003","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.immuni.2010.08.017","article-title":"The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche","volume":"33","author":"Omatsu","year":"2010","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/jbmr.4282","article-title":"Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow","volume":"36","author":"Matsushita","year":"2021","journal-title":"J. Bone Miner. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/ncb3570","article-title":"Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF","volume":"19","author":"Zhou","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e54695","DOI":"10.7554\/eLife.54695","article-title":"Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment","volume":"9","author":"Zhong","year":"2020","journal-title":"eLife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.stem.2016.02.015","article-title":"Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow","volume":"18","author":"Yue","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/jbmr.3340","article-title":"Imbalanced Osteogenesis and Adipogenesis in Mice Deficient in the Chemokine Cxcl12\/Sdf1 in the Bone Mesenchymal Stem\/Progenitor Cells","volume":"33","author":"Tzeng","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1016\/j.stem.2021.08.010","article-title":"Tracing the skeletal progenitor transition during postnatal bone formation","volume":"28","author":"Shu","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/j.cell.2019.04.040","article-title":"A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia","volume":"177","author":"Baryawno","year":"2019","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.celrep.2019.06.031","article-title":"Mapping Distinct Bone Marrow Niche Populations and Their Differentiation Paths","volume":"28","author":"Wolock","year":"2019","journal-title":"Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e108415","DOI":"10.15252\/embj.2021108415","article-title":"Single-cell transcriptomics of LepR-positive skeletal cells reveals heterogeneous stress-dependent stem and progenitor pools","volume":"41","author":"Mo","year":"2022","journal-title":"EMBO J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/(SICI)1526-968X(200004)26:4<225::AID-GENE10>3.0.CO;2-F","article-title":"Identification of a prx1 limb enhancer","volume":"26","author":"Martin","year":"2000","journal-title":"Genesis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/gene.10092","article-title":"Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer","volume":"33","author":"Logan","year":"2002","journal-title":"Genesis"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/S0092-8674(88)91065-3","article-title":"Genes specifically expressed at growth arrest of mammalian cells","volume":"54","author":"Schneider","year":"1988","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Falacho, R.I., Palma, P.J., Marques, J.A., Figueiredo, M.H., Caramelo, F., Dias, I., Viegas, C., and Guerra, F. (2021). Collagenated Porcine Heterologous Bone Grafts: Histomorphometric Evaluation of Bone Formation Using Different Physical Forms in a Rabbit Cancellous Bone Model. Molecules, 26.","DOI":"10.3390\/molecules26051339"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"972","DOI":"10.5603\/FM.a2020.0134","article-title":"Remodelling compartment in root cementum","volume":"80","author":"Rodrigues","year":"2021","journal-title":"Folia Morphol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/ncb3067","article-title":"A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones","volume":"16","author":"Ono","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.cell.2014.11.042","article-title":"Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential","volume":"160","author":"Worthley","year":"2015","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e76932","DOI":"10.7554\/eLife.76932","article-title":"Hypertrophic chondrocytes serve as a reservoir for marrow-associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development","volume":"11","author":"Long","year":"2022","journal-title":"eLife"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"109352","DOI":"10.1016\/j.celrep.2021.109352","article-title":"Regional specialization and fate specification of bone stromal cells in skeletal development","volume":"36","author":"Sivaraj","year":"2021","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41467-018-03124-z","article-title":"Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin","volume":"9","author":"Julien","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/j.stem.2022.10.002","article-title":"Bone marrow and periosteal skeletal stem\/progenitor cells make distinct contributions to bone maintenance and repair","volume":"29","author":"Jeffery","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.stem.2012.02.003","article-title":"Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration","volume":"10","author":"Park","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"19973","DOI":"10.1074\/jbc.M113.454652","article-title":"CCN3 protein participates in bone regeneration as an inhibitory factor","volume":"288","author":"Matsushita","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"29ra30","DOI":"10.1126\/scitranslmed.3000231","article-title":"Wnt proteins promote bone regeneration","volume":"2","author":"Minear","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1146\/annurev.cellbio.20.010403.113126","article-title":"The Wnt signaling pathway in development and disease","volume":"20","author":"Logan","year":"2004","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/jbmr.2318","article-title":"SDF-1\/CXCR4 axis in Tie2-lineage cells including endothelial progenitor cells contributes to bone fracture healing","volume":"30","author":"Kawakami","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/ng1916","article-title":"BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing","volume":"38","author":"Tsuji","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/bies.201200061","article-title":"Control of osteogenesis by the canonical Wnt and BMP pathways in vivo: Cooperation and antagonism between the canonical Wnt and BMP pathways as cells differentiate from osteochondroprogenitors to osteoblasts and osteocytes","volume":"34","author":"Marcellini","year":"2012","journal-title":"Bioessays"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1002\/jbmr.2548","article-title":"BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair","volume":"30","author":"Myers","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1172\/JCI80672","article-title":"NOTCH signaling in skeletal progenitors is critical for fracture repair","volume":"126","author":"Wang","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1101\/gr.253880.119","article-title":"Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging","volume":"29","author":"Kimmel","year":"2019","journal-title":"Genome. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41586-021-03795-7","article-title":"Aged skeletal stem cells generate an inflammatory degenerative niche","volume":"597","author":"Ambrosi","year":"2021","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/j.stem.2021.01.010","article-title":"Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging","volume":"28","author":"Deng","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.stem.2017.02.009","article-title":"Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration","volume":"20","author":"Ambrosi","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.cmet.2017.01.001","article-title":"Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate","volume":"25","author":"Fan","year":"2017","journal-title":"Cell Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1101\/gad.1709008","article-title":"PPARgamma and C\/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale","volume":"22","author":"Lefterova","year":"2008","journal-title":"Genes. Dev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/cdd.2014.80","article-title":"A novel PPAR\u03b32 modulator sLZIP controls the balance between adipogenesis and osteogenesis during mesenchymal stem cell differentiation","volume":"21","author":"Kim","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1006\/bbrc.2000.2981","article-title":"Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro","volume":"273","author":"Kobayashi","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.stem.2010.09.012","article-title":"Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling","volume":"7","author":"Wu","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e13112","DOI":"10.1111\/acel.13112","article-title":"Age-related changes to macrophages are detrimental to fracture healing in mice","volume":"19","author":"Clark","year":"2020","journal-title":"Aging Cell"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Qadir, A., Liang, S., Wu, Z., Chen, Z., Hu, L., and Qian, A. (2020). Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010349"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/nature07848","article-title":"Inactivation of the Fto gene protects from obesity","volume":"458","author":"Fischer","year":"2009","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1002\/jbmr.3729","article-title":"Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans","volume":"34","author":"Farr","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s007740050081","article-title":"Number of osteoprogenitor cells in human bone marrow markedly decreases after skeletal maturation","volume":"17","author":"Nishida","year":"1999","journal-title":"J. Bone Miner. Metab."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1172\/JCI118600","article-title":"Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence","volume":"97","author":"Jilka","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1359\/jbmr.2002.17.2.331","article-title":"Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells","volume":"17","author":"Chen","year":"2002","journal-title":"J. Bone Miner. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41420-022-01048-8","article-title":"BMP9 reduces age-related bone loss in mice by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis","volume":"8","author":"Xu","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/jbmr.2892","article-title":"Identification of Senescent Cells in the Bone Microenvironment","volume":"31","author":"Farr","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1474-9726.2012.00795.x","article-title":"A senescent cell bystander effect: Senescence-induced senescence","volume":"11","author":"Nelson","year":"2012","journal-title":"Aging Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ncb2784","article-title":"A complex secretory program orchestrated by the inflammasome controls paracrine senescence","volume":"15","author":"Acosta","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12929-017-0321-4","article-title":"Marrow adipocytes inhibit the differentiation of mesenchymal stem cells into osteoblasts via suppressing BMP-signaling","volume":"24","author":"Abdallah","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0736-0266(00)00010-3","article-title":"Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors","volume":"19","author":"Muschler","year":"2001","journal-title":"J. Orthop. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1359\/jbmr.1999.14.7.1115","article-title":"Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow","volume":"14","author":"Schiller","year":"1999","journal-title":"J. Bone Miner. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.metabol.2016.11.013","article-title":"Mechanisms of marrow adiposity and its implications for skeletal health","volume":"67","author":"Rosen","year":"2017","journal-title":"Metabolism"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.stem.2012.04.009","article-title":"Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs","volume":"11","author":"Ye","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e13247","DOI":"10.1111\/acel.13247","article-title":"Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice","volume":"19","author":"Almeida","year":"2020","journal-title":"Aging Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"944751","DOI":"10.3389\/fendo.2022.944751","article-title":"Circulating Monocytes Act as a Common Trigger for the Calcification Paradox of Osteoporosis and Carotid Atherosclerosis","volume":"13","author":"Zeng","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e2000202","DOI":"10.1002\/bies.202000202","article-title":"Bone regeneration via skeletal cell lineage plasticity: All hands mobilized for emergencies: Quiescent mature skeletal cells can be activated in response to injury and robustly participate in bone regeneration through cellular plasticity","volume":"43","author":"Matsushita","year":"2021","journal-title":"Bioessays"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s40610-015-0018-y","article-title":"Adipose Tissue Residing Progenitors (Adipocyte Lineage Progenitors and Adipose Derived Stem Cells (ADSC)","volume":"1","author":"Berry","year":"2015","journal-title":"Curr. Mol. Biol. Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/s41588-019-0359-1","article-title":"Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis","volume":"51","author":"Rauch","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/acel.12597","article-title":"DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age","volume":"16","author":"Kim","year":"2017","journal-title":"Aging Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature10600","article-title":"Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders","volume":"479","author":"Baker","year":"2011","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:49:11Z","timestamp":1760125751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,6]]},"references-count":98,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24129814"],"URL":"https:\/\/doi.org\/10.3390\/ijms24129814","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,6]]}}}