Interleukin 13 (IL-13)-regulated expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging cartilage

Abstract

Objective The adamalysin metalloproteinase 15 (ADAM15) has been shown to protect against development of osteoarthritis in mice. Here, we have investigated factors that control ADAM15 levels in cartilage. Design Secretomes from wild-type and Adam15 −/− chondrocytes were compared by label-free quantitative mass spectrometry. mRNA was isolated from murine knee joints, either with or without surgical induction of osteoarthritis on male C57BL/6 mice, and the expression of Adam15 and other related genes quantified by RT-qPCR. ADAM15 in human normal and osteoarthritic cartilage was investigated similarly and by fluorescent immunohistochemistry. Cultured HTB94 chondrosarcoma cells were treated with various anabolic and catabolic stimuli, and ADAM15 mRNA and protein levels evaluated. Results There were no significant differences in the secretomes of chondrocytes from WT and Adam15 −/− cartilage. Expression of ADAM15 was not altered in either human or murine osteoarthritic cartilage relative to disease-free controls. However, expression of ADAM15 was markedly reduced upon aging in both species, to the extent that expression in joints of 18-month-old mice was 45-fold lower than in that 4.5-month-old animals. IL-13 increased expression of ADAM15 in HTB94 ​cells by 2.5-fold, while modulators of senescence and autophagy pathways had no effect. Expression of Il13 in the joint was reduced with aging, suggesting this cytokine may control ADAM15 levels in the joint. Conclusion Expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging human and murine joints, possibly due to a concomitant reduction in IL-13 expression. We thus propose IL-13 as a novel factor contributing to increased osteoarthritis risk upon aging.

The role of EDIL3 in maintaining cartilage extracellular matrix and inhibiting osteoarthritis development

“…Studies have confirmed that IL-3, 42 M-CSF, 43 IL-4, 44 and IL-25 45 are involved in chondroprotection and chondrogenesis. Moreover, IL-13, 45 , 46 IL-10, 47 and IL-19 48 have been demonstrated to slow OA progression. IL-12 49 and IL-27 50 also exert anti-inflammatory effects.…”

Potential of secretome of human fetal cartilage progenitor cells as disease modifying agent for osteoarthritis

“…2G and Table S7G). These pathways may underlie the many effects of cellular processes essential to homeostasis, including the cell cycle, cell survival, in ammation, metabolism, and apoptosis in OA progression [34][35][36][37][38][39], where interleukin-4 and interleukin-13 signaling pathways have been shown to underlie cartilage repair during OA progression through anti-in ammatory and chondroprotective mechanism [40][41][42]. The content of ShFCPC, in addition to a possible delivery mechanism through ECM molecules, provides us with an information database for the development of targeted therapeutics for speci c arthritis diseases such as OA.…”

Quantitative Proteomics Reveals That ADAM15 Can Have Proteolytic-Independent Functions in the Steady State

“…ADAM15 belongs to the ADAM family of sheddases, a class of proteinases that are involved in the ectodomain shedding of transmembrane proteins and play a role in a number of biological processes including cell communication [25]. Both in vitro and in vivo studies have indicated a function for ADAM15 in a number of biological processes, including regulation of cartilage homeostasis.…”