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Osteoarthritis(OA)is a degenerative joint disease.Low-grade inflammation plays an important role in the initiation of OA.Low-doses of LPS in the plasma activate chondrocytes and promote the secretion proinflammatory cytokines,leading to secondary inflammation.Blocking OA-associated TLR activation is a promising strategy for the development of suitable therapies.Here,we want to find some bacteria-derived peptides that can block TLR signaling in chondrocytes more efficiently.Based on previous studies,we screened 12 TIR domain-derived peptides for their effects on NF-кB activation induced by LPS,IL-1β or TNF-α in murine ATDC-5 cells.We evaluated their effects on LPS-induced cytokine expression and secretion.Among them,two bacteria-derived peptides,TcpC-DD and TcpB-DD,showed the most potent inhibitory activities.In comparison with TcpB-DD,TcpC-DD exhibited broader TLR-inhibitory specificity during inflammation in chondrocytes.Furthermore,both TcpC-DD and TcpB-DD displayed strong inhibition of LPS-and IL-1β-induced catabolic reactions in chondrocytes.However,only TcpC-DD exhibited obvious suppression of TNF-α-induced catabolism.In conclusion,we identified two novel inhibitory peptides that modulate catabolism in chondrocytes and innate immune responses,and these peptides could be used to develop novel therapeutic strategies for OA.