Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 mu g/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume (P = .0028), Trabecular Number (P = .0076), Trabecular Fractal Dimension (P = .0044), and increasing Trabecular Separation (P = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot.Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of a plasma cell clone in the BM. The main clinical complication of MM is represented by Bone Disease (BD) often determining pathological fractures and increased mortality risk. To date, MMBD treatment is based on molecules able to avoid bone resorption, but many patients continue to fracture; thus, molecules involved in new bone deposition are under investigation. Among these, we focused on irisin, produced by skeletal muscle during physical exercise, which is able to enhance bone mass and accelerate fracture healing in mice, and prevent bone loss in osteoporotic mice. Therefore, by using a mouse model of MM, we demonstrated that irisin improves MM-induced trabecular bone damage, downregulates the expression of the inhibitor of bone formation, Sclerostin, and modulates bone resorption molecules in favor of bone protection. We also found that irisin reduces MM cell invasion in the femoral BM of mice and reduces myeloma cell viability in vitro, presumably by irisin ability to downregulate the expression of Notch 3 and the regulator of cell proliferation Cyclin D1. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot.Graphical AbstractWe thank Servier Medical Art (https://smart.servier.com/) for providing free image software to build the figure.
Irisin prevents trabecular bone damage and tumor invasion in a mouse model of multiple myeloma
Sanesi L.;Storlino G.;Di Gioia S.;Mori G.;Grano M.;Colaianni G.;Colucci S.
2024-01-01
Abstract
Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 mu g/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume (P = .0028), Trabecular Number (P = .0076), Trabecular Fractal Dimension (P = .0044), and increasing Trabecular Separation (P = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot.Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of a plasma cell clone in the BM. The main clinical complication of MM is represented by Bone Disease (BD) often determining pathological fractures and increased mortality risk. To date, MMBD treatment is based on molecules able to avoid bone resorption, but many patients continue to fracture; thus, molecules involved in new bone deposition are under investigation. Among these, we focused on irisin, produced by skeletal muscle during physical exercise, which is able to enhance bone mass and accelerate fracture healing in mice, and prevent bone loss in osteoporotic mice. Therefore, by using a mouse model of MM, we demonstrated that irisin improves MM-induced trabecular bone damage, downregulates the expression of the inhibitor of bone formation, Sclerostin, and modulates bone resorption molecules in favor of bone protection. We also found that irisin reduces MM cell invasion in the femoral BM of mice and reduces myeloma cell viability in vitro, presumably by irisin ability to downregulate the expression of Notch 3 and the regulator of cell proliferation Cyclin D1. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot.Graphical AbstractWe thank Servier Medical Art (https://smart.servier.com/) for providing free image software to build the figure.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
