Bone dysplasia in Hutchinson‐Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations

Abstract

Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic “progerin” protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the LmnaG609G knock‐in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild‐type and KI osteoclasts from marrow‐derived precursors was inhibited by KI osteoblast‐conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild‐type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross‐talk contribute to abnormal bone formation in HGPS mice.

Aged‐vascular niche hinders osteogenesis of mesenchymal stem cells through paracrine repression of Wnt‐axis

“…Micro‐computed tomography (μCT) of tibiae from Prog‐Tg mice revealed a significant reduction in average cortical bone thickness (Ct.Th) of ~14% and ~11% compared to LA‐Tg and Wt controls, respectively (Figure 1a and Table 1 ). This is consistent with the extent of mean Ct.Th decline observed in physiologically aged mice (0.17 mm at 22 weeks to 0.15 mm at 104 weeks) and ubiquitous prematurely aged HGPS mice as well as elderly patients (Cabral et al., 2023 ; Ferguson et al., 2003 ; Whitmarsh et al., 2019 ). Accordingly, bone volume fraction (BV/TV) is significantly reduced if compared to all three control groups indicating a profound effect of endothelial aging on bone (Figure 1a and Table 1 ).…”

“…Hitherto, these effects were described in the context of cumulative aging of BM stem cell niches describing mainly effects on HSCs (Biswas et al, 2023;Brunet et al, 2022;Ho et al, 2019). A hallmark of aging including HGPS premature aging-related changes in bone structure is the loss of bone mass and thinning of the cortex (Cabral et al, 2023;Ferguson et al, 2003;Whitmarsh et al, 2019) (Brunet et al, 2022).…”

“…A hallmark of aging including HGPS premature aging‐related changes in bone structure is the loss of bone mass and thinning of the cortex (Cabral et al., 2023 ; Ferguson et al., 2003 ; Whitmarsh et al., 2019 ). Similar bone loss and cortical thinning outcomes observed in our endothelial progeria aging mouse model highlight the physiological significance of our findings in aging per se demonstrating for the first time a clear role of endothelial aging in bone homeostasis.…”