Transglutaminase 2 is central to induction of the arterial calcification program by smooth muscle cells.
Arterial calcification is a phenotype of vascular repair in atherosclerosis, diabetes, hyperphosphatemic renal failure, and aging. Arterial calcification is modulated by transition of arterial smooth muscle cells (SMCs) from contractile to chondro-osseous differentiation programmed in response to increases in P(i), bone morphogenetic protein-2, and certain other stimuli. Transglutaminase (TG)2 release modulates tissue repair, partly by transamidation-catalyzed covalent crosslinking of extracellular matrix substrates. TG2 regulates cultured SMC differentiation, resistance artery remodeling to vasoconstriction, and atherosclerotic lesion size. Here, TG2 expression was required for the majority of TG activity in mouse and human aortic SMCs. TG2(-/-) SMCs lost the capacity for P(i) donor-induced formation of multicellular bone-like nodules and for increased expression of the type III sodium-dependent P(i) cotransporter Pit-1 and certain osteoblast and chondrocyte genes (tissue-nonspecific alkaline phosphatase, the osteoblast master transcription factor runx2, and chondrocyte-restricted aggrecan), and for P(i) donor- and bone morphogenetic protein-2-induced calcification. Uniquely in TG2(-/-) SMCs, P(i) donor treatment increased expression of the physiological SMC chondro-osseous differentiation and calcification inhibitors osteoprotegerin, matrix Gla protein, and osteopontin. Conversely, TG2(-/-) SMCs, unlike wild-type SMCs, failed to maintain contractile differentiation on laminin. Exogenous catalytically active TG2 augmented calcification by TG2(-/-) SMC in response to P(i) donor treatment. TG2 expression also drove P(i)-stimulated calcification of mouse aortic ring organ cultures, which was suppressed by the TG2 catalytic site-specific inhibitor Boc-DON-Gln-Ile-Val-OMe (10 micromol/L). Our results suggest that TG2 release in injured arteries is critical for programming chondro-osseous SMC differentiation and calcification in response to increased P(i) and bone morphogenetic protein-2.
Johnson
Kristen A
KA
Veterans Affairs Medical Center, University of California at San Diego, La Jolla, USA.
Polewski
Monika
M
Terkeltaub
Robert A
RA
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001158:Arteries / Q000201:enzymology* / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology; D002114:Calcinosis / Q000201:enzymology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009924:Organ Culture Techniques; D053495:Osteopontin / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000097568:Matrix Gla Protein
D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D019204:GTP-Binding Proteins; D007797:Laminin; D053495:Osteopontin; D053244:Osteoprotegerin; D010710:Phosphates; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D000097568:Matrix Gla Protein