The Alamandine/MrgprD as a Key Player in Antiresorptive Effects in an Osteoporosis Experimental Model

The renin-angiotensin system plays a key role in bone metabolism. While the classical renin-angiotensin system axis promotes bone resorption, the counter-regulatory axis, including alamandine via MrgprD receptor, favors bone formation. This study evaluated the therapeutic effects of alamandine in a model of osteoporosis. In vitro, alamandine reduced osteoclast activation and size in a MrgprD receptor-dependent manner. In vivo, ovariectomy-induced osteoporosis reduced bone parameters, and alamandine reversed trabecular bone loss in wild-type mice but not in MrgprD knockout mice, demonstrating the essential role of the receptor. Alamandine also reduced serum calcium and phosphorus levels in ovariectomized wild-type mice, with no effect on ovariectomized knockout animals. Furthermore, modulation of iron levels differed between genotypes, suggesting the involvement of ferroptosis-related pathways. Histological analysis revealed an increase in the number of osteoblasts and osteocytes in wild-type mice treated with alamandine, corroborating its role in osteogenic differentiation, possibly via the AMPK/eNOS pathway. In contrast, alamandine exacerbated bone resorption in ovariectomized MrgprD knockout mice, potentially through alternative renin-angiotensin system receptors. In conclusion, alamandine increases bone formation and reduces resorption through MrgprD receptor signaling, highlighting its potential as a therapeutic agent in osteoporosis.