Irisin prevents trabecular bone damage and tumor invasion in a mouse model of multiple myeloma
Roberta Zerlotin1, Angela Oranger1, Patrizia Pignataro2
1Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy.
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 μg/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.
Insights
Irisin, a myokine, shows promise in treating multiple myeloma bone disease (MMBD) by improving bone structure and reducing myeloma cell growth. This study demonstrates irisin
Area of Science:
- Bone Biology and Disease
- Myeloma Research
- Endocrinology
Background:
- Multiple myeloma (MM) causes osteolytic bone lesions and fractures, a major complication impacting patient survival.
- Current treatments for MM-associated bone disease (MMBD) primarily use antiresorptive agents, with osteoanabolic therapies under investigation.
- Irisin, a myokine, has demonstrated bone-enhancing and fracture-healing properties in preclinical models.
Purpose of the Study:
- To investigate the therapeutic potential of irisin in a mouse model of multiple myeloma-associated bone disease (MMBD).
- To evaluate irisin's effects on bone microarchitecture, bone cell signaling, and myeloma cell burden in vivo and in vitro.
Main Methods:
- A mouse model of MM was established via intratibial injection of myeloma cells.
- Mice received weekly recombinant irisin injections for five weeks.
- Bone microarchitecture was assessed using micro-CT; gene expression of bone remodeling markers (Sclerostin, RankL, Opg) and myeloma cell proliferation markers (Notch 3, Cyclin D1) were analyzed.
Main Results:
- Irisin treatment partially prevented MM-induced reductions in trabecular bone volume, number, and fractal dimension, while increasing bone separation.
- Irisin downregulated bone resorption markers (Sclerostin, RankL) and upregulated the bone formation marker (Opg).
- Irisin significantly reduced myeloma cell burden in the femur and showed a trend of reduction in the tibia, correlating with decreased myeloma cell viability in vitro.
Conclusions:
- Irisin demonstrates significant therapeutic potential for multiple myeloma-associated bone disease by preserving bone structure and reducing tumor burden.
- Irisin's mechanism involves modulating bone remodeling pathways and directly inhibiting myeloma cell proliferation.
- Irisin represents a promising dual-action therapeutic strategy for simultaneously addressing MMBD and myeloma progression.
