title: The imbalance between TIMP3 and matrix-degrading enzymes plays an important role in intervertebral disc degeneration.
abstract: It is well-known that one of the most important features of intervertebral disc degeneration (IDD) is the extracellular matrix (ECM) degradation. Collagen and aggrecan are major components of ECM; the degradation of ECM in intervertebral discs (IVDs) is closely related to the activities of collagenase and aggrecanase. TIMP-3 is the most efficient inhibitor of aggrecanase in IVD. However, only few studies focus on the potential relationship between TIMP-3 and IDD. In our study, we found TIMP-3 gene expression was decreased after stimulating with LPS in rat nucleus pulposus (NP) cells. Then we used a lentivirus vector to reconstruct rat NP cells which high expressed TIMP-3 gene (LV-TIMP3). The upregulation of MMPs and ADAMTSs induced by LPS was significantly inhibited in LV-TIMP3 cells. After overexpression of TIMP-3, the aggrecan breakdown caused by LPS was also reduced in both monolayer culture and three-dimension culture model. To further study the relation between TIMP-3 and IDD, we collected human NP tissue samples of different degenerative degrees. Real-time PCR and immunohistochemical staining showed that the expression of TIMP-3 was negatively correlated with the degree of intervertebral disc degeneration, while MMP-1 and ADAMTS-4 were markedly increased in degenerative IVD. Taken together, our results suggest that the imbalance between aggrecanase and TIMP-3 may play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target for treating IDD.
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Xiuguo
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Chuanyuan
authors.initials: C
authors.lastname: Mao
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China. Electronic address: medzhaojie@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D055959:Intervertebral Disc Degeneration / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D010450:Endopeptidases; C083641:aggrecanase
keywords: ADAMTS; Aggrecan; Disc degeneration; Nucleus pulposus; TIMP-3