This study is to investigate the possible role of high temperature requirement A 1 (HtrA1) in the articular cartilage degeneration. Paraffin sections were prepared from the knee and temporomandibular (TM) joints of four mouse OA models; two of the models had a genetic mutation (type IX collagen-deficient and type XI collagen-haploinsufficient) and two were surgically induced (destabilization of the medial meniscus of knee joint and discectomy of TM joint). The HtrA1 protein expression profiles of the prepared sections were examined by immunohistostaining. The level of HtrA1 mRNA in the articular cartilage taken from the knee joints of one of the genetically mutated OA models was determined by real-time PCR. Double immunohistostaining was used to examine the expression of co-localization of HtrA1 with type VI collagen and HtrA1 with discoidin domain receptor 2 (Ddr2) in the articular cartilage of knee joints from the genetically mutated OA model. The expression of HtrA1 was found to be increased in the knee and TM joints of these four models at early stages of the disease. An examination of the knee joint of a mutant mouse indicated an 8-fold increase in the level of HtrA1 mRNA, when compared to the levels observed in the knee joints of its wild-type littermates. Pericellular type VI collagen was not present in chondrocytes expressing HtrA1. Meanwhile, the expression of HtrA1 was associated with the expression of Ddr2 in the chondrocytes. Results indicate that HtrA1 may disrupt the pericellular matrix network, resulting in alteration of chondrocyte metabolisms. This eventually leads to OA.