Osteocytes are the main cells in mineralized bone tissue.Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma.However,their precise contribution to bone metastasis rem...Osteocytes are the main cells in mineralized bone tissue.Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma.However,their precise contribution to bone metastasis remains unclear.Here,we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death.Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death.We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis.HMOX1 was identified as a crucial regulatory factor in this process,directly involved in inducing ferroptosis and affecting osteocyte viability.We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation,highlighting the complex relationship between autophagy and ferroptosis in melanoma-induced osteocyte death.In addition,HIF1αpathway was shown as an upstream regulator,providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis.In conclusion,our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis,with a specific focus on ferroptosis and its regulation.This would enhance our comprehension of melanoma-induced osteocyte death.展开更多
基金funding from the European Research Council(ERC)under the european union Horizon 2020 research and innovation program(grant agreement ERC co-LS4 ODE(AB)and ERC Synergy Grant 4D Nanoscope(GS))Deutsche Forschungsgemeinschaft DFG-Project number 501752319-TRR369-DIONE-Project No A02 and B05,FOR 2886(TP02),CRC1181(TPA01)DFG funding(450993414)Thunder Imager and the Leibniz Award(GS)。
文摘Osteocytes are the main cells in mineralized bone tissue.Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma.However,their precise contribution to bone metastasis remains unclear.Here,we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death.Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death.We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis.HMOX1 was identified as a crucial regulatory factor in this process,directly involved in inducing ferroptosis and affecting osteocyte viability.We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation,highlighting the complex relationship between autophagy and ferroptosis in melanoma-induced osteocyte death.In addition,HIF1αpathway was shown as an upstream regulator,providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis.In conclusion,our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis,with a specific focus on ferroptosis and its regulation.This would enhance our comprehension of melanoma-induced osteocyte death.
