Two transglutaminases (TGases), Factor XIIIa and tis- sue TGase (tTGase), are expressed in temporal-spatial association with matrix calcification in growth plates. Meniscal and articular cartilage matrix calcification are prevalent in osteoarthritis (OA) and aging. Here, we demonstrated up-regulation of tTGase and Factor XIIIa in superficial and deep zones of knee OA artic- ular cartilage and the central (chondrocytic) zone of OA menisci. Transforming growth factor-b and inter- leukin (IL)-1b induced Factor XIIIa and tTGase expres- sion in cartilage and meniscal organ cultures. Thus, we studied TGase activity. Donor age-dependent, OA severity-related, and IL-1-induced increases in TGase activity were demonstrated in both knee menisci and cultured meniscal cells. Meniscal cell TGase activity was stimulated by nitric oxide donors and tumor ne- crosis factor-a, but transforming growth factor-b did not stimulate TGase activity. The iNOS inhibitor N- monomethylarginine (NMMA) and an inhibitor of tu- mor necrosis factor receptor-associated factor (TRAF)2 and TRAF6 signaling (the zinc finger protein A20) suppressed IL-1 induction of TGase activity. In- creased Factor XIIIa and tTGase activities, achieved via direct transfection of chondrocytic TC28 and me- niscal cells, both induced matrix apatite deposition. Thus, Factor XIIIa and tTGase activities were in- creased in aging, degenerative cartilages and induced by IL-1. Because TGase activity promoted apatite dep- osition, our findings potentially implicate inflamma- tion in the pathogenesis of cartilage matrix calcifica- tion. (Am J Pathol 2001, 159:149 -163)