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Targeting the Alk4 pathway protects against age-related bone loss
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Activin signaling exacerbates age-related bone loss by inhibiting osteoblast function. Targeting this pathway with Alk4-Fc preserves bone mass and may combat sarcopenia in aging mice.
Area of Science:
- Bone Biology and Aging
- Endocrinology
- Gerontology
Background:
- Osteoporosis is characterized by imbalanced osteoblast and osteoclast activity, leading to bone loss.
- Current therapies primarily target osteoclasts, with limited options for enhancing osteoblast function in aging bone.
- Elevated circulating Activin levels with age suggest a potential role in age-related bone pathologies.
Purpose of the Study:
- To investigate the role of Activin signaling in age-related bone loss.
- To determine if inhibiting Activin signaling can preserve bone mass and osteoblast function in aging mice.
- To explore the potential of targeting Activin for treating osteoporosis and sarcopenia.
Main Methods:
- Assessed Activin signaling and trabecular bone in aging mouse femurs.
- Generated osteoblast-specific Alk4 knockout (cKO) mice to study Activin's effects.
- Administered an Activin ligand trap (Alk4-Fc) to aged mice and evaluated bone and muscle parameters.
Main Results:
- Activin signaling increased with age, correlating with trabecular bone loss.
- Alk4 cKO mice exhibited enhanced bone acquisition, increased osteoblast numbers, and preserved bone formation.
- Alk4-Fc treatment protected against bone loss in femurs and vertebrae and prevented muscle mass decline in aged mice.
Conclusions:
- Circulating Activins play a significant role in inhibiting bone formation and driving age-related bone loss.
- Inhibiting Activin signaling via Alk4 presents a promising therapeutic strategy for osteoporosis.
- Targeting Activin may offer a dual benefit by also addressing age-related muscle loss (sarcopenia).
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