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The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced \u00b5CT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.<\/jats:p>","DOI":"10.1073\/pnas.1906713117","type":"journal-article","created":{"date-parts":[[2020,5,13]],"date-time":"2020-05-13T20:09:40Z","timestamp":1589400580000},"page":"12029-12040","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups"],"prefix":"10.1073","volume":"117","author":[{"given":"Maria B.","family":"Cubria","sequence":"first","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Suarez","sequence":"additional","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidin","family":"Masoudi","sequence":"additional","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Oftadeh","sequence":"additional","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"},{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod","family":"Kamalapathy","sequence":"additional","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"DuBose","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Erdos","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0563-5289","authenticated-orcid":false,"given":"Wayne A.","family":"Cabral","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamya","family":"Karim","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Massachusetts, Dartmouth, MA 02747;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1023-7410","authenticated-orcid":false,"given":"Francis S.","family":"Collins","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"},{"name":"Department of Orthopedic Surgery, Boston Children\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ara","family":"Nazarian","sequence":"additional","affiliation":[{"name":"Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;"},{"name":"Department of Orthopaedic Surgery, Yerevan State Medical University, 0025 Yerevan, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,5,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1056\/NEJMoa0706898","article-title":"Phenotype and course of Hutchinson-Gilford progeria syndrome","volume":"358","author":"Merideth M. 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