Osteoporosis is a chronic skeletal disease characterized by low bone mass and microarchitectural deterioration, resulting in increased fracture risk and reduced quality of life. Given its progressive nature and the involvement of chronic inflammation, there is growing interest in targeting the bone–immune axis for therapeutic innovation. In this study, we investigated the regenerative and immunomodulatory potential of a bioengineered secretome—collected as conditioned media (CM)—from Mesenchymal Stem Cells (MSCs) in which key genes of the NF-κB signalling pathway (IKKβ and NIK) were transiently silenced using LNA-based antisense oligonucleotides (GapmeRs).
The resulting human and mouse secretomes (h/mCM-IKKβ and h/mCM-NIK) were tested across a range of in vitro and ex vivo models relevant to bone biology and inflammation. Both mCM-Ikkβ and mCM-Nik significantly enhance the polarization of M0 macrophages towards the anti-inflammatory M2 phenotype, indicating immunomodulatory capacity. Regarding osteogenesis, CM of human and murine MSCs where Nik/NIK has been silenced, enhanced mineralization and osteogenic gene expression in murine pre-osteoblasts and in human MSCs derived from osteoporotic patients. Conversely, hCM-IKKβ did not increase mineralization but was effective in reducing the RANKL/OPG ratio in human osteoporotic bone explants, suggesting a shift towards anti-resorptive activity.
Altogether, our findings demonstrate that selective inhibition of NF-κB components in MSCs alters their secretory profile in ways that enhance bone formation or suppress bone resorption, depending on the target. This study supports the development of personalized, cell-free therapies based on engineered MSC-derived secretomes for the treatment of osteoporosis.
