Conotoxins from Sea Snails Venom as Potential Bone Remodeling Disruptors

Bone remodeling is a highly regulated process that involves the coordinated activity of bone cells to preserve the integrity of the skeletal system. Dysregulation of these processes contributes to the development of bone disorders, including conditions characterized by high bone mass and bone fragility. Despite progress in current therapies, there is a need for new molecules that can modulate bone remodeling. a-Conotoxins are small peptides isolated from the venom sea snails that exhibit high affinity and selectivity for nicotinic acetylcholine receptors (nAChRs). Distinct nAChR subtypes expressed across bone cell populations offer a new approach for investigating the modulation of bone remodeling processes. In this study, we characterized the effects of two synthetic a-conotoxins, sXm1b and sVc1.1, on bone remodeling using in vitro and ex vivo models. The initial assessment showed dose-dependent cytotoxicity in the bone marrow cells. Confirmatory analysis of a7 and a9 nAChR subunit expression in osteoblasts and osteoclasts provided insight into potential molecular interactions. Transcriptomic analysis revealed differential gene expression patterns in osteoblasts and osteoclasts after a-conotoxin treatment, suggesting modulation of key biological processes for cell differentiation and activity. In vitro functional evaluations demonstrated increased osteoclastogenesis and resorption along with decreased differentiation and mineralization by osteoblasts. Ex vivo cultures of hemicalvarias showed a significant decrease in bone area, an increase in the number of osteoclasts, and modulation of the expression of osteoclast and osteoblast gene markers. Our study characterized the potential of a-conotoxins, sXm1b and sVc1.1, as modulators of bone remodeling processes, affecting osteoclast, osteoblast, and osteocyte activities.