Abstract
The ocean provides food and shelter to diverse marine species, and it is an exceptional source of potential bioactive natural products with promising medicinal properties. Among these, α-conotoxins from venom sea snails show tremendous potential. Our study characterized the effects of synthetic α-conotoxins, sXm1b and sVc1.1, on bone remodeling. Transcriptomic analysis showed significant modulation of critical biological processes, leading to increased osteoclast activity and decreased osteoblast mineralization. sXm1b and sVc1.1 treatment also promoted genes involved in osteoblast and osteoclast proliferation. Interestingly, sVC1.1 showed higher osteoclast gene modulation and reduced the expression of genes critical for osteoblast development and differentiation. In vitro, functional evaluations demonstrated increased osteoclastogenesis and resorption, along with decreased differentiation and mineralization by osteoblasts. In a 3D ex vivo calvaria culture model, these conotoxins significantly decreased bone area, increased osteoclast number, and modulated the expression of osteoclast- and osteoblast-related genes. The findings highlight the promise of α-conotoxins as modulators of bone remodeling for treating non-genetic bone mass accumulation problems while also cautioning about potential adverse effects on bone in individuals undergoing conotoxin therapy for pain management.