title: Distinct transglutaminase 2-independent and transglutaminase 2-dependent pathways mediate articular chondrocyte hypertrophy.
abstract: Altered chondrocyte differentiation, including development of chondrocyte hypertrophy, mediates osteoarthritis and pathologic articular cartilage matrix calcification. Similar changes in endochondral chondrocyte differentiation are essential for physiologic growth plate mineralization. In both articular and growth plate cartilages, chondrocyte hypertrophy is associated with up-regulated expression of certain protein-crosslinking enzymes (transglutaminases (TGs)) including the unique dual-functioning TG and GTPase TG2. Here, we tested if TG2 directly mediates the development of chondrocyte hypertrophic differentiation. To do so, we employed normal bovine chondrocytes and mouse knee chondrocytes from recently described TG2 knockout mice, which are phenotypically normal. We treated chondrocytes with the osteoarthritis mediator IL-1 beta, with the all-trans form of retinoic acid (ATRA), which promotes endochondral chondrocyte hypertrophy and pathologic calcification, and with C-type natriuretic peptide, an essential factor in endochondral development. IL-1 beta and ATRA induced TG transamidation activity and calcification in wild-type but not in TG2 (-/-) mouse knee chondrocytes. In addition, ATRA induced multiple features of hypertrophic differentiation (including type X collagen, alkaline phosphatase, and MMP-13), and these effects required TG2. Significantly, TG2 (-/-) chondrocytes lost the capacity for ATRA-induced expression of Cbfa1, a transcription factor necessary for ATRA-induced chondrocyte hypertrophy. Finally, C-type natriuretic peptide, which did not modulate TG activity, comparably promoted Cbfa1 expression and hypertrophy (without associated calcification) in TG2 (+/+) and TG2 (-/-) chondrocytes. Thus, distinct TG2-independent and TG2-dependent mechanisms promote Cbfa1 expression, articular chondrocyte hypertrophy, and calcification. TG2 is a potential site for intervention in pathologic calcification promoted by IL-1 beta and ATRA.
authors.affiliation: Veterans Affairs Medical Center, University of California San Diego, La Jolla, California 92161, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Deborah
authors.initials: D
authors.lastname: van Etten
authors.forename: Nisha
authors.initials: N
authors.lastname: Nanda
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.forename: Robert A
authors.initials: RA
authors.lastname: Terkeltaub
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002114:Calcinosis / Q000139:chemically induced / Q000473:pathology; D002358:Cartilage, Articular / Q000473:pathology*; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000473:pathology*; D024121:Collagen Type X / Q000235:genetics; D017364:Collagenases / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit; D005121:Extremities; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006984:Hypertrophy; D007375:Interleukin-1 / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology; D009363:Neoplasm Proteins; D010003:Osteoarthritis / Q000139:chemically induced / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D014157:Transcription Factors / Q000235:genetics; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D007375:Interleukin-1; D009363:Neoplasm Proteins; D014157:Transcription Factors; D020098:Natriuretic Peptide, C-Type; D014212:Tretinoin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D000469:Alkaline Phosphatase; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D019204:GTP-Binding Proteins