Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. 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 µCT 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.

Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome

“…Although LMNA G/+ mice appear to lack any detectable bone phenotype at 6 months of age, micro-CT analysis of LMNA G/G mouse femora detected a modest decrease (~5%) in BMD with significant reductions in structural parameters of trabecular and cortical bone, consistent with previous reports (Cubria et al, 2020). This aspect of the HGPS phenotype appears to be due to defective modeling of bone tissue, since bone-and cartilage-specific Osx-driven expression of progerin leads to skeletal abnormalities associated with impaired osteoblast differentiation and loss of the osteocyte population in bone tissue (Schmidt et al, 2012).…”

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

“…Fibroblasts from these mice also have abnormal nuclear morphology that is reversible by pharmacological blockage of protein farnesylation, which is also the case for human and mouse cells expressing progerin or deficient in ZMPSTE24 (38). Notably, however, Lmna L648R/L648R mice have dramatically greater longevity (~1.5 to > 2 years) as compared to Zmpste24 -/mice (4-7 months) (9,10) and Lmna mouse models of HGPS that have 2 mutant alleles encoding progerin (4-10 months) (26,27,29,39). Because Lmna L648R/L648R mice do not die prematurely, and can live more than 2 years, they are an ideal model for studying the effects of permanently farnesylated prelamin A in the context of physiologic aging.…”

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

“…These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations, and probably represent the most reliable progeria mouse model [23]. More recently, the G608G transgene model was bred to homozygosity, resulting in an HGPS mouse model that replicates many aspects of both musculoskeletal and vascular changes of HGPS human patients [24].…”