Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,...Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,the role of M-CSF in arthritic bone erosion is not completely understood.Here,we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS,a receptor for M-CSF,leading to the generation of FMS intracellular domain(FICD)fragments.Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses.Moreover,myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model.The FICD formed a complex with DAP5,and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATcl protein expression.Moreover,targeting the MNK1/2 pathway diminished arthritic bone erosion.These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.展开更多
The hallmarks of spondyloarthritis(SpA)are type 3 immunity-driven inflammation and new bone formation(NBF).Macrophage migration inhibitory factor(MIF)was found to be a key driver of the pathogenesis of SpA by amplifyi...The hallmarks of spondyloarthritis(SpA)are type 3 immunity-driven inflammation and new bone formation(NBF).Macrophage migration inhibitory factor(MIF)was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity,yet MIF-interacting molecules and networks remain elusive.Herein,we identified hypoxia-inducible factor-1 alpha(HIF1A)as an interacting partner molecule of MIF that drives SpA pathologies,including inflammation and NBF.HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG(curdlan-SKG)mice compared to the respective controls.Under hypoxic conditions in which HIF1A was stabilized,human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23,an upstream type 3 immunity-related cytokine.Similar to MIF,systemic overexpression of IL-23 induced SpA pathology in SKG mice,while the injection of a HIF1A-selective inhibitor(PX-478)into curdlan-SKG mice prevented or attenuated SpA pathology,as indicated by a marked reduction in the expression of MIF and IL-23.Furthermore,genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF,despite the presence of psoriasis-like dermatitis and blepharitis.We also found that MIF-and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice.These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification.Together,these results provide supporting evidence for an MIF/HIF1A regulatory network,and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.展开更多
基金This work was supported by the National institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)of the NIH under Award Numbers R01 AR069562 and AR073156(to K.H.P.-M.).
文摘Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,the role of M-CSF in arthritic bone erosion is not completely understood.Here,we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS,a receptor for M-CSF,leading to the generation of FMS intracellular domain(FICD)fragments.Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses.Moreover,myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model.The FICD formed a complex with DAP5,and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATcl protein expression.Moreover,targeting the MNK1/2 pathway diminished arthritic bone erosion.These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.
基金supported by grants to NH from the Canadian Institute of Health Research(CIHR)and Arthritis Society(Canada)AN is a recipient of a CIHR fellowship,Spondyloarthritis Research and Treatment Network(SPARTAN)fellowship,Spondyloarthritis Research Consortium of Canada(SPARCC)fellowship,Edward Christie Stevens fellowship+5 种基金S.Fenwick Research fellowship,and Krembil Research Institute fellowship(Canada)IJ was supported in part by funding from the Natural Sciences Research Council(NSERC#203475)Canada Foundation for Innovation(CFI#225404,#30865)Ontario Research Fund(RDI#34876,RE010-020)IBM and Ian Lawson van Toch Fund.THK was supported by funding from the National Research Foundation(NRF)of Korea(NRF-2021R1A6A1A03038899)the Korea Healthy Industry Development Institute(HI23C0661).
文摘The hallmarks of spondyloarthritis(SpA)are type 3 immunity-driven inflammation and new bone formation(NBF).Macrophage migration inhibitory factor(MIF)was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity,yet MIF-interacting molecules and networks remain elusive.Herein,we identified hypoxia-inducible factor-1 alpha(HIF1A)as an interacting partner molecule of MIF that drives SpA pathologies,including inflammation and NBF.HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG(curdlan-SKG)mice compared to the respective controls.Under hypoxic conditions in which HIF1A was stabilized,human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23,an upstream type 3 immunity-related cytokine.Similar to MIF,systemic overexpression of IL-23 induced SpA pathology in SKG mice,while the injection of a HIF1A-selective inhibitor(PX-478)into curdlan-SKG mice prevented or attenuated SpA pathology,as indicated by a marked reduction in the expression of MIF and IL-23.Furthermore,genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF,despite the presence of psoriasis-like dermatitis and blepharitis.We also found that MIF-and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice.These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification.Together,these results provide supporting evidence for an MIF/HIF1A regulatory network,and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.