Whole‐Body Metabolism and the Musculoskeletal Impacts of Targeting Activin A and Myostatin in Severe Osteogenesis Imperfecta

Abstract

Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygous oim/oim mice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF-β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole-body metabolism effect of treating 5-weekold wildtype (Wt) and oim/oim mice for 11 weeks with either control antibody (Ctrl-Ab) or monoclonal anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab), or a combination of ActA-Ab and Mstn-Ab (Combo). We demonstrated that ActA-Ab treatment minimally impacts muscle mass in oim/oim mice, whereas Mstn-Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment in oim/oim mice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice.

Targeting bone homeostasis regulation: potential of traditional Chinese medicine flavonoids in the treatment of osteoporosis

“…In maintaining bone homeostasis, it regulates the replication and differentiation of chondrocytes, OBs and OCs, which play crucial roles in bone formation and mineralization. Furthermore, the TGF-β superfamily has a significant impact on the bone structure ( Omosule et al, 2023 ). OPG/RANKL/RANK is a major signaling pathway mediating bone resorption/bone formation.…”

Myostatin and Activin A as Biomarkers of Sarcopenia in Inflammatory Bowel Disease Patients

“…It is now well known that many other organs and tissues are the source of their synthesis, including the pituitary gland, thyroid gland, bone marrow, pancreas, adrenal cortex, liver, and the reproductive organs [ 41 , 43 ]. Studies have demonstrated an involvement of activin A (Act A) in tissue inflammatory and repair responses [ 44 , 45 , 46 ]. High levels of this protein were observed in cancer patients, especially in cachectic individuals, which implies its association not only with increased inflammation but also with cachexia [ 47 ].…”