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 anabolic agents are available in current practice, their use remains limited by timing and cost of treatment. Here, we showed that in mouse femurs, levels of Smad2/3 pathway activation progressively increase with age and strongly correlate with early-onset trabecular bone loss. When we deleted Alk4, a Type I receptor activator of Smad2/3, in osteoblast progenitors and in mature osteoblasts, female mice exhibit increased trabecular bone volume and male mice show a partial protection against early-onset trabecular bone loss. These results indicate that Sma2/3 activation through Alk4 inhibits bone formation by osteoblasts and is likely associated with osteoporosis. Interestingly, RNAseq performed on osteoblast progenitors revealed that genes regulated by the Smad2/3 pathway are highly conserved regardless of the activating ligand (Activin A, GDF8, GDF11, or TGFBeta). Our preclinical studies using Alk4-Fc and TGFBeta antibody further showed that bone mass can be increased by targeting TGFBeta in young mice and Activin A in older mice. 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