Type 2 diabetes mellitus(T2DM)exacerbates irreversible bone loss in periodontitis,but the mechanism of impaired bone regeneration caused by the abnormal metabolic process of T2DM remains unclear.Exosomes are regarded ...Type 2 diabetes mellitus(T2DM)exacerbates irreversible bone loss in periodontitis,but the mechanism of impaired bone regeneration caused by the abnormal metabolic process of T2DM remains unclear.Exosomes are regarded as the critical mediator in diabetic impairment of regeneration via organ or tissue communication.Here,we find that abnormally elevated exosomes derived from metabolically impaired liver in T2DM are significantly enriched in the periodontal region and induced pyroptosis of periodontal ligament cells(PDLCs).Mechanistically,fatty acid synthase(Fasn),the main differentially expressed molecule in diabetic exosomes results in ectopic fatty acid synthesis in PDLCs and activates the cleavage of gasdermin D.Depletion of liver Fasn effectively mitigates pyroptosis of PDLCs and alleviates bone loss.Our findings elucidate the mechanism of exacerbated bone loss in diabetic periodontitis and reveal the exosome-mediated organ communication in the“liver-bone”axis,which shed light on the prevention and treatment of diabetic bone disorders in the future.展开更多
While periodontal (PD) disease is among principal causes of tooth loss worldwide, regulation of concomitant soft and mineralized PD tissues, and PD pathogenesis have not been completely clarified yet. Besides, relevan...While periodontal (PD) disease is among principal causes of tooth loss worldwide, regulation of concomitant soft and mineralized PD tissues, and PD pathogenesis have not been completely clarified yet. Besides, relevant pre-clinical models and in vitro platforms have limitations in simulating human physiology. Here, we have harnessed three-dimensional bioprinting (3DBP) technology for developing a multi-cellular microtissue model resembling PD ligament-alveolar bone (PDL-AB) biointerface for the first time. 3DBP parameters were optimized;the physical, chemical, rheological, mechanical, and thermal properties of the constructs were assessed. Constructs containing gelatin methacryloyl (Gel-MA) and hydroxyapatite-magnetic iron oxide nanoparticles showed higher level of compressive strength when compared with that of Gel-MA constructs. Bioprinted self-supporting microtissue was cultured under flow in a microfluidic platform for >10 days without significant loss of shape fidelity. Confocal microscopy analysis indicated that encapsulated cells were homogenously distributed inside the matrix and preserved their viability for >7 days under microfluidic conditions. Immunofluorescence analysis showed the cohesion of stromal cell surface marker-1+ human PDL fibroblasts containing PDL layer with the osteocalcin+ human osteoblasts containing mineralized layer in time, demonstrating some permeability of the printed constructs to cell migration. Preliminary tetracycline interaction study indicated the uptake of model drug by the cells inside the 3D-microtissue. Also, the non-toxic levels of tetracycline were determined for the encapsulated cells. Thus, the effects of tetracyclines on PDL-AB have clinical significance for treating PD diseases. This 3D-bioprinted multi-cellular periodontal/osteoblastic microtissue model has potential as an in vitro platform for studying processes of the human PDL.展开更多
基金supported by the Major Program of the National Natural Science Foundation of China(81991500,81991502,81991504)Shaanxi provincial key research and development program(2023-ZDLSF-49)the National Postdoctoral Program for Innovative Talents of China(BX20220394).
文摘Type 2 diabetes mellitus(T2DM)exacerbates irreversible bone loss in periodontitis,but the mechanism of impaired bone regeneration caused by the abnormal metabolic process of T2DM remains unclear.Exosomes are regarded as the critical mediator in diabetic impairment of regeneration via organ or tissue communication.Here,we find that abnormally elevated exosomes derived from metabolically impaired liver in T2DM are significantly enriched in the periodontal region and induced pyroptosis of periodontal ligament cells(PDLCs).Mechanistically,fatty acid synthase(Fasn),the main differentially expressed molecule in diabetic exosomes results in ectopic fatty acid synthesis in PDLCs and activates the cleavage of gasdermin D.Depletion of liver Fasn effectively mitigates pyroptosis of PDLCs and alleviates bone loss.Our findings elucidate the mechanism of exacerbated bone loss in diabetic periodontitis and reveal the exosome-mediated organ communication in the“liver-bone”axis,which shed light on the prevention and treatment of diabetic bone disorders in the future.
基金This work was partially supported by a grant from The Scientific and Technological Research Council of Turkey (TUBITAKNo. 117M281).
文摘While periodontal (PD) disease is among principal causes of tooth loss worldwide, regulation of concomitant soft and mineralized PD tissues, and PD pathogenesis have not been completely clarified yet. Besides, relevant pre-clinical models and in vitro platforms have limitations in simulating human physiology. Here, we have harnessed three-dimensional bioprinting (3DBP) technology for developing a multi-cellular microtissue model resembling PD ligament-alveolar bone (PDL-AB) biointerface for the first time. 3DBP parameters were optimized;the physical, chemical, rheological, mechanical, and thermal properties of the constructs were assessed. Constructs containing gelatin methacryloyl (Gel-MA) and hydroxyapatite-magnetic iron oxide nanoparticles showed higher level of compressive strength when compared with that of Gel-MA constructs. Bioprinted self-supporting microtissue was cultured under flow in a microfluidic platform for >10 days without significant loss of shape fidelity. Confocal microscopy analysis indicated that encapsulated cells were homogenously distributed inside the matrix and preserved their viability for >7 days under microfluidic conditions. Immunofluorescence analysis showed the cohesion of stromal cell surface marker-1+ human PDL fibroblasts containing PDL layer with the osteocalcin+ human osteoblasts containing mineralized layer in time, demonstrating some permeability of the printed constructs to cell migration. Preliminary tetracycline interaction study indicated the uptake of model drug by the cells inside the 3D-microtissue. Also, the non-toxic levels of tetracycline were determined for the encapsulated cells. Thus, the effects of tetracyclines on PDL-AB have clinical significance for treating PD diseases. This 3D-bioprinted multi-cellular periodontal/osteoblastic microtissue model has potential as an in vitro platform for studying processes of the human PDL.
