Biology subjects

Maridas, D.

Publications and source records attributed to Maridas, D..

3 recordsLinked to original sources

bioRxiv2026

Activation of PPARγ redirects fibro-adipogenic progenitors to replace ectopic bone with fat in models of fibrodysplasia ossificans progressiva and trauma-induced heterotopic ossification

The pathologic, osteogenic differentiation of fibroadipogenic progenitor cells (FAPs) is the primary recognized contributor to ectopic bone formation in fibrodysplasia ossificans progressiva (FOP) and trauma-induced heterotopic ossification (HO). Both conditions are characterized by up-regulated BMP signaling - the former by a gene mutation rendering the BMP receptor ACVR1 susceptible to activation by inflammatory ligands (Activin A), and the latter by up-regulated presence of BMP2 ligand in the setting of unmutated BMP receptor. We performed an unbiased assessment of FDA-approved therapies which would optimally target the transcriptional aberrations observed in developing FOP and HO lesions based on publicly-available datasets. This analysis uncovered rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist as the highest scoring therapeutic option across three data sets for both conditions. Rosiglitazone treatment eliminated ectopic bone lesions in a mouse model of FOP, and replaced these lesions with ectopic adipose tissue; similarly, systemic and local rosiglitazone treatment eliminated ectopic bone lesions in a mouse model of trauma-induced HO and replaced these lesions with ectopic adipose tissue. Our findings were corroborated by a single case report from 2010 showing positive results with rosiglitazone in a non-diabetic patient with FOP, with no subsequent studies. Overall, our findings suggest that a previously FDA-approved therapeutic is likely to be a successful therapeutic agent for both FOP and trauma-induced HO, both conditions for which current therapeutic options remain inadequate. One Sentence SummaryWe show that a previously FDA-approved therapeutic known to induce adipogenesis reduces ectopic bone and induces ectopic fat formation in diseases of heterotopic ossification.

cell biology↗

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

Complex regulatory interactions at GDF5 shape joint morphology and osteoarthritis disease risk

Our ability to pinpoint causal variants using GWAS is dependent on understanding the dynamic epigenomic and epistatic context of each associated locus. Being the best studied skeletal locus, GDF5 associates with many diseases and has a complex cis-regulatory architecture. We interrogate GDF5 regulatory interactions and model disease variants in vitro and in vivo. For all regulatory regions we see that local epigenetic activation/repression impacts patterns of joint-specific expression and disease risk. By modeling the most cited risk variant in mice we found that it had no impact on expression, joint morphology, or disease. Yet, we identified significant epistatic expression interactions between this risk variant and others lying within regulatory regions subject to repression or activation. These findings are important lessons on how regulatory interactions and local epistasis work in the etiology of disease risk, and that assessment of individual variants of high GWAS significance need not alone be considered causal. TeaserGenetic interactions at the most studied skeletal disease locus reveal hidden complexities in pinpointing causal mutations.

genetics↗