title: Deletion of ADAMTS5 does not affect aggrecan or versican degradation but promotes glucose uptake and proteoglycan synthesis in murine adipose derived stromal cells.
abstract: ADAMTS5 (TS5), a member of the aggrecanase clade (TS1, 4, 5, 8, 9, 15) of ADAMTS-proteases, has been considered largely responsible for the proteolysis of the hyalectans, aggrecan (Acan) and versican (Vcan), in vivo. However, we have reported that ts5-knockout (KO) mice show joint protection after injury due to inhibition of synovial scarring and enhanced Acan deposition. Also, KO mice have an impaired wound healing phenotype in skin and tendons which is associated with Acan/Vcan-rich deposits at the wound sites. Moreover, the Acan and Vcan deposited was aggrecanase-cleaved, even in the absence of TS5. In this study, we have used adipose-derived stromal cell (ADSC) and epiphyseal chondrocyte cultures from wild type and KO mice to further study the role of TS5 in Acan and Vcan turnover. We have confirmed with both cell types that the aggrecanase-mediated degradation of these hyalectans is not due to TS5, but an aggrecanase which primarily cleaves them before they are secreted. We also provide data which suggests that TS5 protein functions to suppress glucose uptake in ADSCs and thereby inhibits the synthesis, and promotes the intracellular degradation of Acan and Vcan by an ADAMTS other than TS5. We propose that this apparently non-proteolytic role of TS5 explains its anti-chondrogenic and pro-fibrotic effects in murine models of wound repair. A possible role for TS5 in an endocytotic process, involving competitive interactions between TS5, LRP1 and GLUT4 is discussed.
authors.affiliation: Dept. of Biochemistry, Rush Medical Center, Chicago, IL, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gorski
authors.affiliation: Dept. of Internal Medicine (Rheumatology), Rush Medical Center, Chicago, IL, USA; Dept. of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Dept. of Internal Medicine (Rheumatology), Rush Medical Center, Chicago, IL, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Dept. of Internal Medicine (Rheumatology), Rush Medical Center, Chicago, IL, USA; Dept. of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lauer
authors.affiliation: Equine Orthopedic Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kisiday
authors.affiliation: Dept. of Biochemistry, Rush Medical Center, Chicago, IL, USA; Dept. of Internal Medicine (Rheumatology), Rush Medical Center, Chicago, IL, USA. Electronic address: Anna_Plaas-Sandy@rush.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Plaas
authors.affiliation: Dept. of Biochemistry, Rush Medical Center, Chicago, IL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sandy
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071116:ADAMTS5 Protein; D050153:Abdominal Fat / Q000166:cytology; D053674:Aggrecans / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011509:Proteoglycans / Q000096:biosynthesis*; D059748:Proteolysis; D011973:Receptors, LDL / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D053675:Versicans / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011509:Proteoglycans; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C508323:Vcan protein, mouse; D053675:Versicans; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D005947:Glucose
keywords: ADAMTS5; ADAMTS5 knock out; Adipose derived stromal cells; Aggrecan; Degradation; Hyaluronan; Mesenchymal stem cells; Versican