title: The NLRP3/Caspase-1/Interleukin-1β Axis Is Active in Human Lumbar Cartilaginous Endplate Degeneration.
abstract: BACKGROUND
  Modic changes are the MRI signal changes of degenerative lumbar vertebral endplate and which lead to or accelerate intervertebral disc degeneration. NLRP3, caspase-1, and interleukin-1β (IL-1β) play a pivotal role in the pathogenesis of many inflammatory diseases, such as osteoarthritis. However, the roles of IL-1β and its activators caspase-1 and NLRP3 are unclear in the degenerative endplate.
  
  
  OBJECTIVE
  We asked: (1) What are the degenerative changes of the histologic features and chondrogenic markers' gene expressions between the cartilaginous endplates of patients with Modic changes and trauma (control)? (2) How does the NLRP3/caspase-1/IL-1β axis in the cartilaginous endplates of patients with Modic changes compare with control (trauma) specimens?
  
  
  METHODS
  Surgical specimens of cartilaginous endplates were divided into Modic changes (n = 56) and the trauma control (n = 16) groups. Hematoxylin and eosin and safranin O staining of cartilaginous endplate tissues were done to evaluate the extracellular matrix. Reverse transcription-polymerase chain reaction was performed on these tissues to investigate mRNA expression of type II collagen (Col II), SOX-9, matrix metalloproteinase-3, and a disintegrin like and metalloproteinase thrombospondin type I motifs-5. NLRP3, caspase-1, and IL-1β were evaluated by reverse transcription-polymerase chain reaction and immunohistochemistry.
  
  
  RESULTS
  Hematoxylin and eosin and safranin O staining showed the extracellular matrix degraded in the cartilaginous endplates of patients with Modic changes but not in the control cartilaginous endplates. Chondrogenic Col II (p = 0.024) and SOX9 (p = 0.053) were downregulated in the Modic changes group compared with the control group. In contrast to the control group, the transcriptional levels of NLRP3 (p < 0.001), caspase-1 (p = 0.054), and IL-1β (p = 0.001) were all upregulated in the Modic changes group.
  
  
  CONCLUSIONS
  The expression of NLRP3, caspase-1, and IL-1β was upregulated in the patients with low back pain and Modic changes on MRI compared with patients with vertebral burst fracture without degenerative changes on MRI. The data suggest the NLRP3/caspase-1/IL-1β axis may be implicated in lumbar cartilaginous endplate degeneration.
  
  
  CONCLUSIONS
  The NLRP3/caspase-1/IL-1β axis is active in cartilaginous endplates of patients with Modic changes and inflammatory cascades can exacerbate the cartilaginous endplate degeneration which may act as a trigger for intervertebral disc degeneration and low back pain. If these findings can be confirmed by others, we hope that new and effective therapy could be developed directed against this target.
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, #3 East Qingchun Road, Hangzhou, 310016, China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Tang
authors.affiliation: Department of Orthopaedics, Yiwu Chowzhou Hospital, Yiwu, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Orthopaedics, Lishui People's Hospital, Lishui, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Ji
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, #3 East Qingchun Road, Hangzhou, 310016, China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, #3 East Qingchun Road, Hangzhou, 310016, China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, #3 East Qingchun Road, Hangzhou, 310016, China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
authors.forename: Shun-Wu
authors.initials: SW
authors.lastname: Fan
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, #3 East Qingchun Road, Hangzhou, 310016, China. hzj.163.com@163.com.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China. hzj.163.com@163.com.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D016022:Case-Control Studies; D020170:Caspase 1 / Q000032:analysis* / Q000235:genetics; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000032:analysis* / Q000235:genetics; D008159:Lumbar Vertebrae / Q000201:enzymology* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013122:Spinal Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; D020170:Caspase 1