Chim, S. M. | bioRxiv Science

bioRxiv2025

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

Osteoporosis is a chronic age-related condition in which imbalanced activities between bone-forming osteoblasts and bone-resorbing osteoclasts lead to the progressive loss of bone volume and quality. While drugs that target osteoclastic activity have been developed, there remains a lack of efficient therapies that increase osteoblast number and function in aging bones. Here, we investigated if Activin, known to increase in the circulation with age, plays a primary role in bone loss associated with aging. We showed that, in mouse femurs, levels of Activin signaling progressively increased with age and strongly correlated with the loss of trabecular bone. Furthermore, mice lacking the type I receptor for Activin, namely Alk4, in osteoblast progenitors (Alk4 cKO mice) had increased trabecular bone acquisition, osteoblast number, and bone formation rate. In addition, Alk4 cKO male mice were protected against early age-related trabecular bone loss observed at 1 year of age. These results indicate that Activin signaling inhibits bone formation and osteoblast activity and is likely associated with osteoporosis. To further test this, we injected 2-year-old male mice with a ligand trap (Alk4-Fc) to capture circulating Activin. Alk4-Fc protected against loss of trabecular bone in femurs and L5 vertebrae. Interestingly, Alk4-Fc also prevented a decrease in muscle mass in gastrocnemius, quadriceps, and triceps suggesting 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 loss and can be efficiently targeted to alleviate osteoporosis and sarcopenia in aging mice. One Sentence SummaryIn this study, we discovered a new way of preserving trabecular bone mass in aging mice by inhibiting activity of Alk4 pathway.

cell biology↗

bioRxiv2024

A Human Brain-Chip for modelling brain pathologies and screening of BBB crossing therapeutic strategies

The limited translatability of preclinical experimental findings to human patients remains an obstacle for successful treatment of brain diseases. Relevant models to elucidate mechanisms behind brain pathogenesis, such as human cell-based systems, and support successful targeting and prediction of drug responses in humans are in urgent need given the species differences in brain and blood-brain barrier (BBB) functions. Here, we examined and advanced a Brain-Chip which recapitulates aspects of the human cortical parenchyma and the BBB in one model. We utilized human primary astrocytes and pericytes, hiPSC-derived cortical neurons, hiPSC-derived brain microvascular endothelial-like cells, and included for the first time on chip hiPSC-derived microglia. Using TNF to emulate neuroinflammation, we demonstrate that our model recapitulates in vivo-relevant responses. Importantly, we show microglia-derived responses, highlighting the ability of the model to capture cell-specific contributions in human disease associated pathology. We next tested BBB crossing of human transferrin receptor antibodies and conjugated adeno-associated viruses, and demonstrate successful in vitro/in vivo correlation in identifying crossing differences. These findings highlight the potential of the Brain-Chip as a time-saving and reliable model to support therapeutic development for brain diseases.

bioengineering↗