본문 바로가기
KERD
논문KCI 등재

Fibulin2: a negative regulator of BMSC osteogenic differentiation in infected bone fracture healing

Yang Jing|Jiang Hao|Li Shi-Dan|Xing Wei|Wang Shao-Chuan|Li You-Bin|Zheng Han-Xuan|Li Xiao-Ming|Guo De-Bin|Xie Xiao-Yu|Jiang Ren-Qing|Fan Chao|Li Lei|Xu Xiang|Fei Jun
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2023.12|Experimental and Molecular Medicine|제55권 |pp. 443-456|DOI 10.1038/s12276-023-00942-0

0

조회

0

다운로드

1

인용

0

참고문헌

주제분류생화학

초록

Bone fracture remains a common occurrence, with a population-weighted incidence of approximately 3.21 per 1000. In addition, approximately 2% to 50% of patients with skeletal fractures will develop an infection, one of the causes of disordered bone healing. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays a key role in disordered bone repair. However, the specific mechanisms underlying BMSC dysfunction caused by bone infection are largely unknown. In this study, we discovered that Fibulin2 expression was upregulated in infected bone tissues and that BMSCs were the source of infection-induced Fibulin2. Importantly, Fibulin2 knockout accelerated mineralized bone formation during skeletal development and inhibited inflammatory bone resorption. We demonstrated that Fibulin2 suppressed BMSC osteogenic differentiation by binding to Notch2 and inactivating the Notch2 signaling pathway. Moreover, Fibulin2 knockdown restored Notch2 pathway activation and promoted BMSC osteogenesis; these outcomes were abolished by DAPT, a Notch inhibitor. Furthermore, transplanted Fibulin2 knockdown BMSCs displayed better bone repair potential in vivo. Altogether, Fibulin2 is a negative regulator of BMSC osteogenic differentiation that inhibits osteogenesis by inactivating the Notch2 signaling pathway in infected bone.

Abstract

Bone fracture remains a common occurrence, with a population-weighted incidence of approximately 3.21 per 1000. In addition, approximately 2% to 50% of patients with skeletal fractures will develop an infection, one of the causes of disordered bone healing. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays a key role in disordered bone repair. However, the specific mechanisms underlying BMSC dysfunction caused by bone infection are largely unknown. In this study, we discovered that Fibulin2 expression was upregulated in infected bone tissues and that BMSCs were the source of infection-induced Fibulin2. Importantly, Fibulin2 knockout accelerated mineralized bone formation during skeletal development and inhibited inflammatory bone resorption. We demonstrated that Fibulin2 suppressed BMSC osteogenic differentiation by binding to Notch2 and inactivating the Notch2 signaling pathway. Moreover, Fibulin2 knockdown restored Notch2 pathway activation and promoted BMSC osteogenesis; these outcomes were abolished by DAPT, a Notch inhibitor. Furthermore, transplanted Fibulin2 knockdown BMSCs displayed better bone repair potential in vivo. Altogether, Fibulin2 is a negative regulator of BMSC osteogenic differentiation that inhibits osteogenesis by inactivating the Notch2 signaling pathway in infected bone.

참고문헌 (56)

  1. Hao, M. L., "Gut microbiota : an overlooked factor that plays a significant role in osteoporosis", J. Int. Med. Res, 47, pp.4095~4103 (2019)
  2. Huang, D. F., "Bone fragility, fracture risk and trauma : a complicated triangle in children", Acta Ortop. Bras, 25, pp.99~102 (2017)
  3. Gong, Y., "Comparison of the effects of minimally invasive percutaneous pedicle screws osteosynthesis and open surgery on repairing the pain, inflammation and recovery of thoracolumbar vertebra fracture", Exp. Ther. Med, 14, pp.4091~4096 (2017)
  4. Liu, M., "IFT80 is required for fracture healing through controlling the regulation of TGF-beta signaling in chondrocyte differentiation and function", J. Bone Miner. Res, 35, pp.571~582 (2020)
  5. Chen, W., "National incidence of traumatic fractures in China : a retrospective survey of 512 187 individuals", Lancet Glob. Health, 5, pp.e807~e817 (2017)
  6. Cottrell, J. A., "The biology of bone and ligament healing", Foot Ankle. Clin, 21, pp.739~761 (2016)
  7. Rupp, M., "Do systemic factors influence the fate of nonunions to become atrophic? A retrospective analysis of 162 cases", Biomed. Res. Int, 2019, pp.6407098~ (2019)
  8. Szelerski, L., "The outcomes of Ilizarov treatment in aseptic nonunions of the tibia stratified by treatment strategies and surgical techniques", Sci. Rep, 10, pp.20511~ (2020)
  9. Martini, F., "Bone morphogenetic protein-2 signaling in the osteogenic differentiation of human bone marrow mesenchymal stem cells induced by pulsed electromagnetic fields", Int. J. Mol. Sci, 21, pp.2104~ (2020)
  10. Urish, K. L., "Staphylococcus aureus osteomyelitis: bone, bugs, and surgery", Infect. Immun, 88, pp.e00932-19~ (2020)
  11. Cassat, J. E., "A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis", Cell Host Microbe, 13, pp.759~772 (2013)
  12. Nandi, S. K., "Understanding osteomyelitis and its treatment through local drug delivery system", Biotechnol. Adv, 34, pp.1305~1317 (2016)
  13. Tang, R., "Interleukin-37 inhibits osteoclastogenesis and alleviates inflammatory bone destruction", J. Cell Physiol, 234, pp.7645~7658 (2019)
  14. Loi, F., "Inflammation, fracture and bone repair", Bone, 86, pp.119~130 (2016)
  15. Li, D., "Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation", Nat. Commun, 7, pp.10872~ (2016)
  16. Pesce Viglietti, A. I., "Proinflammatory microenvironment during kingella kingae infection modulates osteoclastogenesis", Front. Immunol, 12, pp.757827~ (2021)
  17. Wang, J., "Roles for miRNAs in osteogenic differentiation of bone marrow mesenchymal stem cells", Stem Cell Res. Ther, 10, pp.197~ (2019)
  18. Du, F., "Comparison of concentrated fresh mononuclear cells and cultured mesenchymal stem cells from bone marrow for bone regeneration", Stem Cells Transl. Med, 10, pp.598~609 (2021)
  19. Luo, Z. W., "Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration", Nanoscale, 11, pp.20884~20892 (2019)
  20. Kavanagh, N., "Staphylococcal osteomyelitis : disease progression, treatment challenges, and future directions", Clin. Microbiol. Rev, 31, pp.e00084-17~ (2018)
  21. Li, S., "A clinical diagnostic study : fibulin-2 is a novel promising biomarker for predicting infection", Infect. Dis. Ther, 11, pp.1057~1073 (2022)
  22. Zhang, H., "Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-beta signalling", Clin. Sci, 126, pp.275~288 (2014)
  23. Kluge, M., "Characterization of a novel calciumbinding 90-kDa glycoprotein(BM-90)shared by basement membranes and serum", Eur. J. Biochem, 193, pp.651~659 (1990)
  24. Yi, C. H., "Loss of fibulin-2expression is associated with breast cancer progression", Am. J. Pathol, 170, pp.1535~1545 (2007)
  25. Sakamoto, K., "Distinct roles of EGF repeats for the Notch signaling system", Exp. Cell Res, 302, pp.281~291 (2005)
  26. Suckling, R. J., "Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands", EMBO J, 36, pp.2204~2215 (2017)
  27. Hu, B., "Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling", Cancer Res, 72, pp.3873~3885 (2012)
  28. Majidinia, M., "The roles of signaling pathways in bone repair and regeneration", J. Cell. Physiol, 233, pp.2937~2948 (2018)
  29. Fujita, Y., "Acetylation of NDPK-D regulates its subcellular localization and cell survival", PLoS ONE, 10, pp.e0139616~ (2015)
  30. Jeong, S. J., "Anti-vascular endothelial growth factor antibody attenuates inflammation and decreases mortality in an experimental model of severe sepsis", Crit. Care, 17, pp.R97~ (2013)
  31. McLeod, M. J., "Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizarin red S", Teratology, 22, pp.299~301 (1980)
  32. Viswanathan, S., "Mesenchymal stem versus stromal cells : International Society for Cell & Gene Therapy(ISCT(R))Mesenchymal Stromal Cell committee position statement on nomenclature", Cytotherapy, 21, pp.1019~1024 (2019)
  33. Ma, Y., "Cadmium toxicity : a role in bone cell function and teeth development", Sci. Total Environ, 769, pp.144646~ (2021)
  34. Li, H., "KR-12-a5 reverses adverse effects of lipopolysaccharides on HBMSC osteogenic differentiation by influencing BMP", Smad and P38 MAPK signaling pathways, 2019, pp.10, 639~
  35. Schweisguth, F., "Regulation of notch signaling activity", Curr. Biol, 14, pp.R129~R138 (2004)
  36. Tanaka, E., "Notch2 activation ameliorates nephrosis", Nat. Commun, 5, pp.3296~ (2014)
  37. Ongaro, A., "Characterization of notch signaling during osteogenic differentiation in human osteosarcoma cell line MG63", J. Cell Physiol, 231, pp.2652~2663 (2016)
  38. Venkatesan, A., "In silico and experimental validation of protein-protein interactions between PknI and Rv2159c from Mycobacterium tuberculosis", J. Mol. Graph. Model, 62, pp.283~293 (2015)
  39. Pierce, B. G., "Accelerating protein docking in ZDOCK using an advanced 3D convolution library", PLoS ONE, 6, pp.e24657~ (2011)
  40. Joeng, K. S., "Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis", J. Clin. Investig, 127, pp.2678~2688 (2017)
  41. Chen, H., "The osteocyte plays multiple roles in bone remodeling and mineral homeostasis", Med. Mol. Morphol, 48, pp.61~68 (2015)
  42. Kong, L., "Macrophages in bone homeostasis", Curr. Stem Cell Res. Ther, 14, pp.474~481 (2019)
  43. Yang, J., "Diallyl disulfide alleviates inflammatory osteolysis by suppressing osteoclastogenesis via NF-kappaB-NFATc1 signal pathway", FASEB J, 33, pp.7261~7273 (2019)
  44. Wang, Y., "Staphylococcal protein A promotes osteoclastogenesis through MAPK signaling during bone infection", J. Cell Physiol, 232, pp.2396~2406 (2017)
  45. Sato, T., "Peptidoglycan of Actinomyces naeslundii induces inflammatory cytokine production and stimulates osteoclastogenesis in alveolar bone resorption", Arch. Oral. Biol, 57, pp.1522~1528 (2012)
  46. Wan, D. C., "Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation", J. Biol. Chem, 282, pp.26450~26459 (2007)
  47. Mundy, C., "Connective tissue growth factor(CTGF", CCN2)negatively regulates BMP-2 induced osteoblast differentiation and signaling, 2014, pp.229, 672~681
  48. Nistala, H., "Fibrillin-1 and-2 differentially modulate endogenous TGF-beta and BMP bioavailability during bone formation", J. Cell Biol, 190, pp.1107~1121 (2010)
  49. Cooley, M. A., "Fibulin-1 is required for bone formation and Bmp-2-mediated induction of Osterix", Bone, 69, pp.30~38 (2014)
  50. Tsuda, T., "Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction", J. Mol. Cell Cardiol, 52, pp.273~282 (2012)
  51. Takeuchi, H., "Site-specific O-glucosylation of the epidermal growth factor-like(EGF)repeats of notch : efficiency of glycosylation is affected by proper folding and amino acid sequence of individual EGF repeats", J. Biol. Chem, 287, pp.33934~33944 (2012)
  52. Lee, J. S., "HES1 cooperates with pRb to activate RUNX2-dependent transcription", J. Bone Miner. Res, 21, pp.921~933 (2006)
  53. Manokawinchoke, J., "NOTCH2 participates in Jagged1-induced osteogenic differentiation in human periodontal ligament cells", Sci. Rep, 10, pp.13329~ (2020)
  54. Vollersen, N., "High bone turnover in mice carrying a pathogenic Notch2mutation causing Hajdu-Cheney Syndrome", J. Bone Miner. Res, 33, pp.70~83 (2018)
  55. Yorgan, T., "Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton", Bone, 87, pp.136~146 (2016)
  56. Zhu, F., "PKCdelta is required for Jagged-1induction of human mesenchymal stem cell osteogenic differentiation", Stem Cells, 31, pp.1181~1192 (2013)

관련 논문AI추천

Role of Wnt signaling in fracture healingDandan Ning, Huiyun Xu, Jean X. Jiang, Jingbao Li, Jing Duan, Peng Shang, Ruixin Yang, Ruofei Liu생화학분자생물학회 · BMB Reports2014 · 제47권 제12호Dickkopf-1 is involved in BMP9-induced osteoblast differentiation of C3H10T1/2 mesenchymal stem cellsJie Hao, Jieliang Shen, Ji Fang, Liangbo Lin, Nian Zhou, Quanhe Qiu, Wei Jiang, Wen Dong, Zhenming Hu생화학분자생물학회 · BMB Reports2016 · 제49권 제3호Benefits of lumican on human bone health: clinical evidence using bone marrow aspiratesBeom-Jun Kim, Eunah Choi, Jin Young Lee, So Jeong Park, Yun Sun Lee대한내과학회 · The Korean Journal of Internal Medicine2022 · 제37권 제4호IGF1 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells through the enhancement of BMP/Smad signalingChang-Jun Pi, Liang Chen, Liangjun Yin, Nian Wu, Ran-Xi Zhang, Xiang Zou, Zhong-Liang Deng생화학분자생물학회 · BMB Reports2016 · 제49권 제2호Transforming Growth Factor-β Signaling Inhibits the Osteogenic Differentiation of Mesenchymal Stem Cells via Activation of Wnt/β-Catenin PathwayAzita Parvaneh Tafreshi대한골대사학회 · 대한골대사학회지2025 · 제32권 제1호Foxf2 represses bone formation via Wnt2b/β-catenin signalingCarlsson Peter, Inose Hiroyuki, Ito Yoshiaki, Jingquan Chen, Kato Tsuyoshi, Kobayashi Yutaka, Ochi Hiroki, Okawa Atsushi, Saito Masanori, Sato Shingo, Takahashi Akira, Tanaka Tomoyuki, Xiaolong Sun, Yoshii Toshitaka생화학분자생물학회 · Experimental and Molecular Medicine2022 · 제54권

이 간행물의 다른 논문 (225건)

Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics김성영, Han Yeaeunpp. 1-12Grave-to-cradle: human embryonic lineage tracing from the postmortem bodyKu Eu Jeong, Choi Seock Hwan, Choi Yujin Angelina, Oh Ji Wonpp. 13-21Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesisKim Tae-Hee, Loe Adrian Kwan Ho, Zhu Lexinpp. 22-31TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cellsCha Hyuk-Jin, Kim Yun-Jeong, Go Young-Hyun, 정호창, Kwon Eun-Ji, Kim Seong-Min, Cheong Hyun Sub, Kim Wantae, Shin Hyoung Doo, Lee Haeseungpp. 32-42ZBTB7A suppresses glioblastoma tumorigenesis through the transcriptional repression of EPB41L5Nam Hae Yun, 김성학, 김승후, 최경철, Park Seung-Ho, Song Ji-Hye, Jeong Ji-Hoon, Kim Hyunhee, Jeong Minseok, Kong Min-Jeong, Son Jihyun, Jeong Ji-Eunpp. 43-54
원문 보기