1、2014Effects of TNF- on bone homeostasisINDEX1Introduction2Effects of TNF- on bone homeostasis 3TNF- and bone erosion in rheumatoid arthritisBone homeostasisTNF-On osteoclastsOn osteoblastsIntroduction 1Osteoimmunology Osteo-immunology+Interactions of the bone and immune systemOsteoimmunology Takayan

2、agi, H. (2015). SnapShot: Osteoimmunology. Cell Metabolism, 21(3), 502-502.e501. doi:/10.1016/j.cmet.2015.02.001Bone homeostasisOsteoclastOrigin: hematopoieticMultinucleated cellsThe only cells able to resorb boneOsteoblastOrigin: mesenchymal stromal/stem cellsBone-forming cellsOsteocyte Differentia

3、ted from osteoblastsMaintain the bone matrixMaintain the homeostasis of blood Ca2+，PO43-Bone biologyOsteoclastOsteoblastOsteocyte David, J. P., & Schett, G. (2010). TNF and bone. Curr Dir Autoimmun, 11, 135-144. doi:10.1159/000289202 TNFSF & TNFRSFHistory of TNF-Activity described by Carswell, 1975C

4、loned, purified and initially characterized by Aggarwal and colleagues, mid-1980sTwo protein superfamiliesTNF superfamily (TNFSF) 19 ligandsTNF- ,Lymphotoxin-, Lymphotoxin-, CD40L, CD27LTNF receptor superfamily (TNFRSF)29 receptorsTNFR1, TNFR2, OX40, CD40 TNF- and its receptorsTNF-Two forms: transme

5、mbrane & solubleSynthesized by macrophages, T and B lymphocytes, etc. TNF- receptors TNFR1Expressed by almost every mammalian cell type Containing a death domain & coupling TNF- to apoptosis Playing a predominant role in most of the biological effect of TNF-TNFR2Expressed by immune cells, endothelia

6、l cellsFunction of TNF-Regulating pro-inflammatory responses Cellular communication Cell differentiation Cell death OShea, J. J., Ma, A., & Lipsky, P. (2002). Cytokines and autoimmunity. Nat Rev Immunol, 2(1), 37-45. Retrieved from /10.1038/nri702Effects of TNF- on bone homeostasis 2Effect of TNF- o

7、n osteoclastsEssential factors of osteoclast differentiationMacrophage-colony stimulating factor (M-CSF)Binding to c-Fms, a tyrosine kinase receptorPromoting proliferation and survival of the monocyte progenitorsReceptor activator of NF-B ligand (RANKL)Binding to RANK, inducing the synthesis and act

8、ivation of NF-B, AP-1 and NFATc1Drives the monocytes toward premature and mature osteoclastsTeitelbaum, S. L., & Ross, F. P. (2003). Genetic regulation of osteoclast development and function. Nat Rev Genet, 4(8), 638-649. Retrieved from /10.1038/nrg1122Osta, B., Benedetti, G., & Miossec, P. (2014).

9、Classical and paradoxical effects of TNF- on bone homeostasis. Frontiers in Immunology, 5. doi:10.3389/fimmu.2014.00048Effect of TNF- on osteoclasts differentiation Directly Binding to TNFR1By stimulating NF-B, JNK and p38 Combination with IL-1 Indirectly By stimulating RANKL-induced osteoclastogene

10、sis by increasing the level of expression of RANKMoelants, E. A. V., Mortier, A., Van Damme, J., & Proost, P. (2013). Regulation of TNF-alpha with a focus on rheumatoid arthritis. Immunol Cell Biol, 91(6), 393-401. doi:10.1038/icb.2013.15Effect of TNF- on osteoblasts Blockage of osteoblast different

11、iationInhibiting the expression of Runx2 Runx2 : major transcription factor for osteoblast differentiationInhibiting runx2 transcriptionDestabilizing its messengerPromoting degradation of Runx2 proteinInhibiting OsxOsx: downstream target of Runx2, major transcription factor for osteoblast differenti

12、ationInterfering with Wnt signalingEffect of TNF- on different stages of osteoblastogenesis David, J. P., & Schett, G. (2010). TNF and bone. Curr Dir Autoimmun, 11, 135-144. doi:10.1159/000289202Effect of TNF- on osteoblasts Stimulatory effect on early stage of osteogenesisBy increasing BMP-2 expres

13、sion in human mesenchymal stem cells (hMSC)Dose-specific effects on osteogenic differentiation of MSCTNF- and bone erosion in rheumatoid arthritis3Rheumatoid arthritisSymptoms Synovial inflammation and hyperplasia (“swelling”)Autoantibody production (rheumatoid factor and anticitrullinated protein a

14、ntibody ACPA)Cartilage and bone destruction (“deformity”)Most distinctive radiographic sign of joint damageDiagnostic and prognostic valueSystemic features, including cardiovascular, pulmonary, psychological, and skeletal disordersSwellingDeformityRheumatoid arthritisMcInnes IB, Schett G. N Engl J M

15、ed 2011;365:2205-2219.The role of TNF- in RAActivates leukocytes, endothelial cells, and synovial fibroblasts, inducing production of cytokines, chemokines, adhesion molecules, and matrix enzymesSuppression of regulatory T-cell functionActivation of osteoclasts and resorption of cartilage and boneMe

16、diates metabolic and cognitive dysfunctionEffect of TNF- in bone erosion of RAAutoantibodies against citrullinated proteins & osteoclastogenesisSchett, G., & Gravallese, E. (2012). Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol, 8(11), 656-664. doi:10.10

17、38/nrrheum.2012.153The role of TNF- in bone erosion of RADisruption of bone homeostasis by synovitisSchett, G., & Gravallese, E. (2012). Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol, 8(11), 656-664. doi:10.1038/nrrheum.2012.153Anti-TNF therapyMcInnes I

18、B, Schett G. N Engl J Med 2011;365:2205-2219.Clinical studiesSBMD: bone mineral density Manara, M., & Sinigaglia, L. (2015). Bone and TNF in rheumatoid arthritis: clinical implications. RMD Open, 1(Suppl 1), e000065. doi:10.1136/rmdopen-2015-000065Clinical studiesConclusionAlmost all studies demonst

19、rated that treatment with anti-TNF could arrest the decrease of BMD related to the disease and sometimes even increase BMD values.QuestionWhether the effect of anti-TNF therapy on BMD is due only to clinical inflammation suppression or is also related to a specific TNF inhibition？Clinical studies: a

20、nti-TNF therapy vs traditional DMARD Traditional disease-modifying antirheumatic drug (DMARD)Immunosuppressive drugs other than glucocorticoids to slow down disease progressionTwo large RCT BeSt trialFactors associated with hand bone loss: radiographic disease progression, postmenopausal status, and

21、 inflammation Supporting the hypothesis that anti-TNF therapy decreases bone loss through tight control of disease activityPREMIER trial Factors associated with hand bone loss: no use of adalimumab, increasing age, and inflammationSuggesting that the benefits of anti-TNF therapy may not be limited t

22、o control of inflammation, but also to the ability to block the direct effect of TNF on osteoclast activationConclusion TNF-Important role in the regulation of bone homeostasisInducer of osteoclastogenesis and inhibitor of osteoblastogenesis Complex signaling pathwaysSuccessful clinical application

23、QuestionsOsteogenic differentiation effects in vivo?Effect in other diseases?New drug?ReferencesBrenner, D., Blaser, H., & Mak, T. W. (2015). Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol, 15(6), 362-374. doi:10.1038/nri3834Danks, L., & Takayanagi, H. (2013). Immu

24、nology and bone. J Biochem, 154(1), 29-39. doi:10.1093/jb/mvt049David, J. P., & Schett, G. (2010). TNF and bone. Curr Dir Autoimmun, 11, 135-144. doi:10.1159/000289202Feng, X. (2005). Regulatory roles and molecular signaling of TNF family members in osteoclasts. Gene, 350(1), 1-13. doi:/10.1016/j.ge

25、ne.2005.01.014Kawai, V. K., Stein, C. M., Perrien, D. S., & Griffin, M. R. (2012). Effects of anti-tumor necrosis factor alpha agents on bone. Curr Opin Rheumatol, 24(5), 576-585. doi:10.1097/BOR.0b013e328356d212Kotake, S., & Nanke, Y. (2014). Effect of TNFalpha on osteoblastogenesis from mesenchyma

26、l stem cells. Biochim Biophys Acta, 1840(3), 1209-1213. doi:10.1016/j.bbagen.2013.12.013Lorenzo, J., Horowitz, M., & Choi, Y. (2008). Osteoimmunology: interactions of the bone and immune system. Endocr Rev, 29(4), 403-440. doi:10.1210/er.2007-0038Manara, M., & Sinigaglia, L. (2015). Bone and TNF in

27、rheumatoid arthritis: clinical implications. RMD Open, 1(Suppl 1), e000065. doi:10.1136/rmdopen-2015-000065Moelants, E. A. V., Mortier, A., Van Damme, J., & Proost, P. (2013). Regulation of TNF-alpha with a focus on rheumatoid arthritis. Immunol Cell Biol, 91(6), 393-401. doi:10.1038/icb.2013.15OShea, J. J., Ma, A., & Lipsky, P. (2002). Cytokines and