title: Leptin downregulates aggrecan through the p38-ADAMST pathway in human nucleus pulposus cells.
abstract: The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD.
authors.affiliation: Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Xicheng District, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Jinqian
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong.
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Shen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D053674:Aggrecans / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D007403:Intervertebral Disc / Q000378:metabolism; D055959:Intervertebral Disc Degeneration / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D053674:Aggrecans; D020738:Leptin; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins