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Targeting the Alk4 pathway protects against age-related bone loss.

ABSTRACT: Osteoporosis is a chronic age-related condition where imbalanced activities between bone-forming osteoblasts and bone-resorbing osteoclasts result in the progressive loss of bone volume and reduced bone quality. While drugs that target osteoclast activity have been developed, there remains a lack of efficient therapies that increase osteoblast function in aging bones. Here, we showed that in mouse femurs, levels of Activin signaling progressively increased with age and strongly correlated with the loss of trabecular bone. When we removed Alk4, the type I receptor for Activin in osteoblast progenitors, Alk4 cKO mice had increased numbers of osteoblasts, an increased rate of bone formation, and increased trabecular bone acquisition. These results indicate that Activin through Alk4 signaling inhibits bone formation and osteoblast activity and is likely associated with osteoporosis. Furthermore, when we injected 2-year-old male mice with Alk4-Fc to capture circulating Activin, aged mice were protected against loss of trabecular bone in both femurs and L5 vertebrae. Remarkably, Alk4-Fc also prevented the age-related decrease in muscle mass that normally accompanies age-related bone loss, indicating that circulating Activins also play a role in sarcopenia. In summary, our preclinical mouse models reveal that circulating Activins play a primary role in age-related bone and muscle loss and can be efficiently targeted to alleviate osteoporosis and sarcopenia in aging mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE315968 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder that affects 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 a toxic protein termed “progerin”. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects and bone dysplasia. In this study 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 cortical and trabecular bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated underlying mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild-type and KI osteoclasts from bone marrow-derived precursors was inhibited in the presence of KI osteoblast-conditioned media in vitro, suggesting an extrinsic factor(s) responsible for the decreased number of TRAcP-positive osteoclasts observed on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced capacity to deposit and mineralize extracellular matrix and increased lipid accumulation compared to wild-type, providing a mechanism for the reduced mineral apposition and bone formation rates observed in vivo. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. These data demonstrate that osteoblast phenotypic plasticity, rather than dysregulated bone remodelling, contributes to abnormal bone formation in HGPS mice.

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Targeting the Alk4 pathway protects against age-related bone loss.

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