Ataxia-televangelist mutated (ATM)/ ATR serine/threonine kinase (ATR)-mediated RAD51 recombinase (RAD51) promotes osteogenic differentiation and inhibits osteoclastogenesis in osteoporosis

ABSTRACT Osteoporosis is a metabolic bone disease that significantly affects the quality of life and can even lead to death. In this study, we aimed to investigate the role of RAD51 recombinase (RAD51) in osteoblast and osteoclast differentiation. We analyzed differentially expressed genes using microarray analysis. The osteogenic differentiation capability was analyzed by alkaline phosphatase (ALP) staining and alizarin red staining assays. Osteogenesis and osteoclast related genes expression was detected using quantitative real-time PCR (qPCR) and Western blotting. The phosphorylation of Ataxia-telangiectasia mutated (ATM) and ATR serine/threonine kinase (ATR) was tested using Western blotting. The effect of RAD51 on osteoporosis was also explored in vivo. The results showed that RAD51 was downregulated in osteoporosis, but upregulated in differentiated osteoblasts. Overexpression of RAD51 enhanced the differentiation of osteoblasts and suppressed the formation of osteoclasts. Furthermore, p-ATM and p-ATR levels were upregulated in osteoblasts and downregulated in osteoclasts. RAD51 expression was reduced by the ATM/ATR pathway inhibitor AZ20. AZ20 treatment inhibited osteoblastogenesis and promoted osteoclastogenesis, whereas RAD51 reversed the effects induced by AZ20. Moreover, RAD51 improved bone microarchitecture in vivo. Taken together, ATM/ATR signaling-mediated RAD51 promoted osteogenic differentiation and suppressed osteoclastogenesis. These findings reveal a critical role for RAD51 in osteoporosis.

[1]  A. Qian,et al.  Role of Biomolecules in Osteoclasts and Their Therapeutic Potential for Osteoporosis , 2021, Biomolecules.

[2]  Yuan-Hua Chen,et al.  Identification of Rad51 as a prognostic biomarker correlated with immune infiltration in hepatocellular carcinoma , 2021, Bioengineered.

[3]  Ding-wei Cang,et al.  Circular RNA_0062582 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via regulation of microRNA-145/CBFB axis , 2021, Bioengineered.

[4]  M. Guo,et al.  Epigenetic based synthetic lethal strategies in human cancers , 2020, Biomarker research.

[5]  F. Esashi,et al.  RAD51: Beyond the break , 2020, Seminars in cell & developmental biology.

[6]  M. Greenblatt,et al.  Osteoblast-Osteoclast Communication and Bone Homeostasis , 2020, Cells.

[7]  N. Martins,et al.  Telomeres, DNA Damage and Ageing: Potential Leads from Ayurvedic Rasayana (Anti-Ageing) Drugs , 2020, Journal of clinical medicine.

[8]  P. Pietschmann,et al.  PATHOPHYSIOLOGY AND THERAPEUTIC OPTIONS , 2020 .

[9]  B. Bouvard,et al.  Osteoporosis in older adults. , 2021, Joint bone spine.

[10]  Sarah R. Hengel,et al.  RAD51 Gene Family Structure and Function. , 2020, Annual review of genetics.

[11]  L. Schurgers,et al.  Early vascular ageing in chronic kidney disease: impact of inflammation, vitamin K, senescence and genomic damage , 2020, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[12]  S. Zha,et al.  ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion , 2020, Cell & Bioscience.

[13]  E. Laurini,et al.  Role of Rad51 and DNA repair in cancer: A molecular perspective. , 2020, Pharmacology & therapeutics.

[14]  K. Sugimoto,et al.  Activation of ATR-related protein kinase upon DNA damage recognition , 2019, Current Genetics.

[15]  Chao Li,et al.  Silencing of LncRNA-ANCR Promotes the Osteogenesis of Osteoblast Cells in Postmenopausal Osteoporosis via Targeting EZH2 and RUNX2 , 2019, Yonsei medical journal.

[16]  S. Meng,et al.  MiR-125a-5p promotes osteoclastogenesis by targeting TNFRSF1B , 2019, Cellular & molecular biology letters.

[17]  Jie Liu,et al.  Vitamin K2 stimulates MC3T3-E1 osteoblast differentiation and mineralization through autophagy induction , 2019, Molecular medicine reports.

[18]  R. Cha,et al.  Versatility of the Mec1ATM/ATR signaling network in mediating resistance to replication, genotoxic, and proteotoxic stresses , 2019, Current Genetics.

[19]  R. Ung,et al.  Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture , 2018, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  A. Cifu,et al.  Treatment of Osteoporosis. , 2018, JAMA.

[21]  Z. Wang,et al.  The effect of icariin on bone metabolism and its potential clinical application , 2018, Osteoporosis International.

[22]  Zhuojing Luo,et al.  Screening and validation of serum protein biomarkers for early postmenopausal osteoporosis diagnosis. , 2017, Molecular medicine reports.

[23]  R. Eastell,et al.  Use of bone turnover markers in postmenopausal osteoporosis. , 2017, The lancet. Diabetes & endocrinology.

[24]  Carolyn Brown.  Staying strong , 2017, Nature.

[25]  S. Jackson,et al.  ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. , 2017, Molecular cell.

[26]  K. Bashir,et al.  Upregulation of RAD51 expression is associated with progression of thyroid carcinoma. , 2017, Experimental and molecular pathology.

[27]  Z. Lou,et al.  A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination , 2016, Genes & development.

[28]  C. Sørensen,et al.  ATM/ATR‐mediated phosphorylation of PALB2 promotes RAD51 function , 2016, EMBO reports.

[29]  Mingyao Liu,et al.  LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption , 2016, Nature Medicine.

[30]  Stephen K. Godin,et al.  Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication. , 2016, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[31]  P. Miller.  Management of severe osteoporosis , 2016, Expert opinion on pharmacotherapy.

[32]  Bo Chen,et al.  Natural products for treatment of osteoporosis: The effects and mechanisms on promoting osteoblast-mediated bone formation. , 2016, Life sciences.

[33]  J. Surrallés,et al.  Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. , 2015, Current opinion in genetics & development.

[34]  M. Jasin,et al.  Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. , 2015, Cold Spring Harbor perspectives in biology.

[35]  Andreas Hochwagen,et al.  A non-sister act: recombination template choice during meiosis. , 2014, Experimental cell research.

[36]  K. Schröder.  NADPH oxidases in bone homeostasis and osteoporosis. , 2019, Free radical biology & medicine.

[37]  K. Schröder.  NADPH oxidases in bone homeostasis and osteoporosis , 2014, Cellular and Molecular Life Sciences.

[38]  D. Ferguson,et al.  Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms. , 2013, Human molecular genetics.

[39]  Wolf-Dietrich Heyer,et al.  Homologous recombination in DNA repair and DNA damage tolerance , 2008, Cell Research.

[40]  Xueying Wang,et al.  Genetic Studies of Bone Diseases: Evidence for Involvement of DNA Damage Response Proteins in Bone Remodeling , 2007, International journal of biomedical science : IJBS.