A Missense Variant in TP53 Could Be a Genetic Biomarker Associated with Bone Tissue Alterations
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Micro-Computed Tomography (μCT)
4.3. Sample Processing and RNA Extraction
4.4. Reverse Transcription and Real-Time Quantitative PCR
4.5. Enzyme-Linked Immunosorbent Assay
4.6. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Weitzmann, M.N.; Ofotokun, I. Physiological and pathophysiological bone turnover—Role of the immune system. Nat. Rev. Endocrinol. 2016, 12, 518–532. [Google Scholar] [CrossRef] [PubMed]
- Kanis, J.A. Diagnosis of osteoporosis. Osteoporos. Int. 1997, 7 (Suppl. 3), S108–S116. [Google Scholar] [CrossRef]
- Yang, T.L.; Shen, H.; Liu, A.; Dong, S.S.; Zhang, L.; Deng, F.Y.; Zhao, Q.; Deng, H.W. A road map for understanding molecular and genetic determinants of osteoporosis. Nat. Rev. Endocrinol. 2020, 16, 91–103. [Google Scholar] [CrossRef] [PubMed]
- Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 2007, 13, 791–801. [Google Scholar] [CrossRef] [PubMed]
- Siris, E.S.; Miller, P.D.; Barrett-Connor, E.; Faulkner, K.G.; Wehren, L.E.; Abbott, T.A.; Berger, M.L.; Santora, A.C.; Sherwood, L.M. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: Results from the National Osteoporosis Risk Assessment. JAMA 2001, 286, 2815–2822. [Google Scholar] [CrossRef]
- Kanis, J.A. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002, 359, 1929–1936. Available online: https://pubmed.ncbi.nlm.nih.gov/12057569/ (accessed on 26 May 2023). [CrossRef] [PubMed]
- Adachi, J.D.; Adami, S.; Gehlbach, S.; Anderson, F.A.; Boonen, S.; Chapurlat, R.D.; Compston, J.E.; Cooper, C.; Delmas, P.; Diez-Perez, A.; et al. Impact of prevalent fractures on quality of life: Baseline results from the global longitudinal study of osteoporosis in women. Mayo Clin. Proc. 2010, 85, 806–813. [Google Scholar] [CrossRef]
- Kanis, J.A.; Johansson, H.; Odén, A.; Johnell, O.; De Laet, C.E.; Eisman, J.A.; McCloskey, E.V.; Mellstrom, D.; Melton, L.J., III; Pols, H.A.; et al. A family history of fracture and fracture risk: A meta-analysis. Bone 2004, 35, 1029–1037. [Google Scholar] [CrossRef]
- Ralston, S.H.; Uitterlinden, A.G. Genetics of Osteoporosis. Endocr. Rev. 2010, 31, 629–662. [Google Scholar] [CrossRef]
- Trajanoska, K.; Rivadeneira, F. The genetic architecture of osteoporosis and fracture risk. Bone 2019, 126, 2–10. [Google Scholar] [CrossRef]
- Mitek, T.; Nagraba, Ł.; Deszczyński, J.; Stolarczyk, M.; Kuchar, E.; Stolarczyk, A. Genetic Predisposition for Osteoporosis and Fractures in Postmenopausal Women. Adv. Exp. Med. Biol. 2019, 1211, 17–24. [Google Scholar] [PubMed]
- Koromani, F.; Trajanoska, K.; Rivadeneira, F.; Oei, L. Recent Advances in the Genetics of Fractures in Osteoporosis. Front. Endocrinol. 2019, 10, 337. [Google Scholar] [CrossRef] [PubMed]
- Zhu, X.; Bai, W.; Zheng, H. Twelve years of GWAS discoveries for osteoporosis and related traits: Advances, challenges and applications. Bone Res. 2021, 9, 23. [Google Scholar] [CrossRef] [PubMed]
- Yu, T.; You, X.; Zhou, H.; Kang, A.; He, W.; Li, Z.; Li, B.; Xia, J.; Zhu, H.; Zhao, Y.; et al. p53 plays a central role in the development of osteoporosis. Aging 2020, 12, 10473–10487. [Google Scholar] [CrossRef] [PubMed]
- Jia, F.; Sun, R.; Li, J.; Li, Q.; Chen, G.; Fu, W. Interactions of Pri-miRNA-34b/c and TP53 Polymorphisms on the Risk of Osteoporosis. Genet. Test. Mol. Biomark. 2016, 20, 398–401. [Google Scholar] [CrossRef] [PubMed]
- Vogelstein, B.; Lane, D.; Levine, A.J. Surfing the p53 network. Nature 2000, 408, 307–310. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Kua, H.Y.; Hu, Y.; Guo, K.; Zeng, Q.; Wu, Q.; Ng, H.H.; Karsenty, G.; de Crombrugghe, B.; Yeh, J.; et al. p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling. J. Cell Biol. 2006, 172, 115–125. [Google Scholar] [CrossRef]
- Liu, H.; Li, B. p53 control of bone remodeling. J. Cell. Biochem. 2010, 111, 529–534. [Google Scholar] [CrossRef]
- Sakamuro, D.; Sabbatini, P.; White, E.; Prendergast, G.C. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 1997, 15, 887–898. [Google Scholar] [CrossRef]
- Bonafé, M.; Salvioli, S.; Barbi, C.; Trapassi, C.; Tocco, F.; Storci, G.; Invidia, L.; Vannini, I.; Rossi, M.; Marzi, E.; et al. The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death. Cell Death Differ. 2004, 11, 962–973. [Google Scholar] [CrossRef]
- Dumont, P.; Leu, J.I.J.; Della Pietra, A.C.; George, D.L.; Murphy, M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat. Genet. 2003, 33, 357–365. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; Qi, M.; Konermann, A.; Zhang, L.; Jin, F.; Jin, Y. The p53/miR-17/Smurf1 pathway mediates skeletal deformities in an age-related model via inhibiting the function of mesenchymal stem cells. Aging 2015, 7, 205–218. [Google Scholar] [CrossRef] [PubMed]
- Yun, J.; Espinoza, I.; Pannuti, A.; Romero, D.; Martinez, L.; Caskey, M.; Stanculescu, A.; Bocchetta, M.; Rizzo, P.; Band, V.; et al. p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating with the Notch Transcriptional Complex via MAML1. J. Cell. Physiol. 2015, 230, 3115–3127. [Google Scholar] [CrossRef] [PubMed]
- Velletri, T.; Huang, Y.; Wang, Y.; Li, Q.; Hu, M.; Xie, N.; Yang, Q.; Chen, X.; Chen, Q.; Shou, P.; et al. Loss of p53 in mesenchymal stem cells promotes alteration of bone remodeling through negative regulation of osteoprotegerin. Cell Death Differ. 2020, 28, 156–169. [Google Scholar] [CrossRef]
- Simonet, W.S.; Lacey, D.L.; Dunstan, C.R.; Kelley, M.C.; Chang, M.S.; Lüthy, R.; Nguyen, H.Q.; Wooden, S.; Bennett, L.; Boone, T.; et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997, 89, 309–319. [Google Scholar] [CrossRef] [PubMed]
- Boyle, W.J.; Simonet, W.S.; Lacey, D.L. Osteoclast differentiation and activation. Nature 2003, 423, 337–342. [Google Scholar] [CrossRef] [PubMed]
- Olivier, M.; Eeles, R.; Hollstein, M.; Khan, M.A.; Harris, C.C.; Hainaut, P. The IARC TP53 database: New online mutation analysis and recommendations to users. Hum. Mutat. 2002, 19, 607–614. [Google Scholar] [CrossRef]
- Pietsch, E.C.; Humbey, O.; Murphy, M.E. Polymorphisms in the p53 pathway. Oncogene 2006, 25, 1602–1611. [Google Scholar] [CrossRef]
- Tian, X.; Dai, S.; Sun, J.; Jiang, S.; Jiang, Y. The association between the TP53 Arg72Pro polymorphism and colorectal cancer: An updated meta-analysis based on 32 studies. Oncotarget 2016, 8, 1156–1165. [Google Scholar] [CrossRef]
- Gomez-Sanchez, J.C.; Delgado-Esteban, M.; Rodriguez-Hernandez, I.; Sobrino, T.; de la Ossa, N.P.; Reverte, S.; Bolaños, J.P.; Gonzalez-Sarmiento, R.; Castillo, J.; Almeida, A. The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke. J. Exp. Med. 2011, 208, 429–437. [Google Scholar] [CrossRef]
- Leu, J.I.J.; Murphy, M.E.; George, D.L. The p53 Codon 72 Polymorphism Modifies the Cellular Response to Inflammatory Challenge in the Liver. J. Liver 2013, 2, 117. [Google Scholar] [PubMed]
- Diakite, B.; Kassogue, Y.; Dolo, G.; Wang, J.; Neuschler, E.; Kassogue, O.; Keita, M.L.; Traore, C.B.; Kamate, B.; Dembele, E.; et al. p.Arg72Pro polymorphism of P53 and breast cancer risk: A meta-analysis of case-control studies. BMC Med. Genet. 2020, 21, 206. [Google Scholar] [CrossRef] [PubMed]
- Usategui-Martín, R.; Lendinez-Tortajada, V.; Pérez-Castrillón, J.L.; Briongos-Figuero, L.; Abadía-Otero, J.; Martín-Vallejo, J.; Lara-Hernandez, F.; Chaves, F.J.; García-Garcia, A.B.; Martín-Escudero, J.C. Polymorphisms in genes involved in inflammation, the NF-kB pathway and the renin-angiotensin-aldosterone system are associated with the risk of osteoporotic fracture. The Hortega Follow-up Study. Bone 2020, 138, 115477. [Google Scholar] [CrossRef] [PubMed]
- Usategui-Martín, R.; Pérez-Castrillón, J.L.; Mansego, M.L.; Lara-Hernández, F.; Manzano, I.; Briongos, L.; Abadía-Otero, J.; Martín-Vallejo, J.; García-García, A.B.; Martín-Escudero, J.C.; et al. Association between genetic variants in oxidative stress-related genes and osteoporotic bone fracture. The Hortega follow-up study. Gene 2022, 809, 146036. [Google Scholar] [CrossRef]
- Frank, A.K.; Julia, I.; Leu, J.; Zhou, Y.; Devarajan, K.; Nedelko, T.; Klein-Szanto, A.; Hollstein, M.; Murphy, M.E. The Codon 72 Polymorphism of p53 Regulates Interaction with NF-κB and Transactivation of Genes Involved in Immunity and Inflammation. Mol. Cell. Biol. 2011, 31, 1201–1213. [Google Scholar] [CrossRef] [PubMed]
- Novack, D.V. Role of NF-κB in the skeleton. Cell Res. 2011, 21, 169–182. [Google Scholar] [CrossRef]
- Boyce, B.F.; Xiu, Y.; Li, J.; Xing, L.; Yao, Z. NF-κB-Mediated Regulation of Osteoclastogenesis. Endocrinol. Metab. 2015, 30, 35–44. [Google Scholar] [CrossRef]
- Farr, J.N.; Khosla, S. Cellular senescence in bone. Bone 2019, 121, 121–133. [Google Scholar] [CrossRef]
- Campbell, G.M.; Sophocleous, A. Quantitative analysis of bone and soft tissue by micro-computed tomography: Applications to ex vivo and in vivo studies. BoneKEy Rep. 2014, 3, 564. [Google Scholar] [CrossRef]
- Van’t Hof, R.J. Analysis of bone architecture in rodents using microcomputed tomography. Methods Mol. Biol. 2012, 816, 461–476. [Google Scholar]
- Livak, K.J.; Schmittgen, T.D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods 2001, 25, 402–408. [Google Scholar] [CrossRef]
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Usategui-Martín, R.; Galindo-Cabello, N.; Pastor-Idoate, S.; Fernández-Gómez, J.M.; del Real, Á.; Ferreño, D.; Lapresa, R.; Martín-Rodriguez, F.; Riancho, J.A.; Almeida, Á.; et al. A Missense Variant in TP53 Could Be a Genetic Biomarker Associated with Bone Tissue Alterations. Int. J. Mol. Sci. 2024, 25, 1395. https://doi.org/10.3390/ijms25031395
Usategui-Martín R, Galindo-Cabello N, Pastor-Idoate S, Fernández-Gómez JM, del Real Á, Ferreño D, Lapresa R, Martín-Rodriguez F, Riancho JA, Almeida Á, et al. A Missense Variant in TP53 Could Be a Genetic Biomarker Associated with Bone Tissue Alterations. International Journal of Molecular Sciences. 2024; 25(3):1395. https://doi.org/10.3390/ijms25031395
Chicago/Turabian StyleUsategui-Martín, Ricardo, Nadia Galindo-Cabello, Salvador Pastor-Idoate, José María Fernández-Gómez, Álvaro del Real, Diego Ferreño, Rebeca Lapresa, Francisco Martín-Rodriguez, José A. Riancho, Ángeles Almeida, and et al. 2024. "A Missense Variant in TP53 Could Be a Genetic Biomarker Associated with Bone Tissue Alterations" International Journal of Molecular Sciences 25, no. 3: 1395. https://doi.org/10.3390/ijms25031395