Harnessing the immune system to treat bone loss: The immunomodulatory and osteoprotective effects of the microalga Skeletonema costatum

The emerging field of osteoimmunology provides compelling evidence for the pivotal role of the immune system in the development of bone erosive pathologies such as osteoporosis. However, no immunomodulatory drug has yet been integrated into the therapeutic management of bone loss. Recently, driven by the demand for next-generation treatments for these conditions, natural compounds are gaining renewed attention as promising candidates for drug discovery. In this study, we explored the anti-osteoclastogenic effects of an emerging extract from the marine microalga Skeletonema costatum. Using a zebrafish model of bone regeneration, we demonstrated the extracts ability to inhibit the recruitment of osteoclast progenitors and block their differentiation into mature osteoclasts in vivo. Bulk RNA sequencing of early-stage fin blastemas revealed the downregulation of genes involved in inflammation, T-cell activation, and antigen presentation, suggesting that the extract exerts its effects primarily through immunomodulatory mechanisms. To further assess its therapeutic potential, we tested the extract in a medaka model of RANKL-induced osteoporosis and on a murine macrophage cell line. The extract effectively prevented bone loss in fish and inhibited osteoclastic differentiation in murine macrophages in vitro. Collectively, our findings provide mechanistic insights into a novel, therapeutically relevant natural extract, offering proof of concept for its osteoprotective potential through immune system modulation. SignificanceRecent findings in the field of osteoimmunology reveal the potential of targeting immune cells to regulate bone homeostasis. However, this approach has yet to be applied to therapies for bone erosive conditions. This study explores the potential of an immunomodulatory strategy using an emerging natural extract, which prevent osteoclast differentiation by modulating inflammation, T-cell activation, and macrophage fate determination in zebrafish and medaka models of bone regeneration and osteoporosis. The extract also inhibits osteoclastic differentiation in a murine macrophage line, suggesting its translatability to mammalian systems. By focusing on immune pathways, this research provides a proof of concept for developing immunomodulatory treatments for osteoporosis and similar conditions, addressing a critical need in bone health management.