In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically ...In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and highthroughput analyses, we demonstrate that prolonged HIF-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice.Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells.The stabilization of HIF-1α protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis.Induction of HSP70 expression by geranylgeranylacetone(GGA) administration alleviates ovariectomy-induced osteoporosis.Moreover, RANKL gene expression has a positive correlation with HIF1 A expression in human B cells. In conclusion, HIF-1αsignaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.展开更多
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
文摘In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and highthroughput analyses, we demonstrate that prolonged HIF-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice.Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells.The stabilization of HIF-1α protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis.Induction of HSP70 expression by geranylgeranylacetone(GGA) administration alleviates ovariectomy-induced osteoporosis.Moreover, RANKL gene expression has a positive correlation with HIF1 A expression in human B cells. In conclusion, HIF-1αsignaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.
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.
