title: Blockade of hypoxia-induced CXCR4 with AMD3100 inhibits production of OA-associated catabolic mediators IL-1β and MMP-13.
abstract: Binding of the chemokine stromal cell-derived factor-1 (SDF-1) to its receptor C-X-C chemokine receptor type 4 (CXCR4) results in receptor activation and the subsequent release of matrix metalloproteinases (MMPs) that contribute to osteoarthritis (OA) cartilage degradation. As hypoxia is a defining feature of the chondrocyte microenvironment, the present study investigated the possible mechanism through which SDF‑1 induces cartilage degradation under hypoxic conditions. To do this, OA chondrocyte cultures and patient tissue explants pretreated with the CXCR4 inhibitor, AMD3100 were incubated with SDF‑1. It was identified that hypoxic conditions significantly elevated the expression of CXCR4 in osteoarthritic chondrocytes relative to normoxic conditions. Furthermore, SDF‑1 elevated MMP‑13 mRNA levels and proteinase activity. It also elevated the mRNA and protein levels of runt‑related transcription factor 2, and induced the release of glycosaminoglycans and the inflammatory cytokine, interleukin‑1β. By contrast, such changes did not occur to an appreciable degree in cells that were pretreated with AMD3100. The results of the present study demonstrate that even under hypoxic conditions, where CXCR4 expression is significantly elevated in chondrocytes, AMD3100 effectively blocks this receptor and protects chondrocytes from OA‑induced catabolism, suggesting that the successful inhibition of CXCR4 may be an effective approach for OA treatment.
authors.affiliation: Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Pengcui
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Chathuraka T
authors.initials: CT
authors.lastname: Jayasuriya
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Jingming
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Foot and Ankle Orthopaedic Surgery Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Foot and Ankle Orthopaedic Surgery Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Wei
mesh_terms: D001596:Benzylamines; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D000080027:Cyclams; D004789:Enzyme Activation; D015870:Gene Expression; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D050659:Core Binding Factor Alpha 1 Subunit; D000080027:Cyclams; D006571:Heterocyclic Compounds; D053583:Interleukin-1beta; D019718:Receptors, CXCR4; D053509:Matrix Metalloproteinase 13; C088327:plerixafor