Articular cartilage degeneration in the contralateral non-surgical temporomandibular joint in mice with a unilateral partial discectomy.

OBJECTIVE: The objective was to characterize the contralateral non-surgical temporomandibular joint (TMJ) in mice that had an opposing osteoarthrosis(OA)-like joint induced by unilateral partial discectomy. METHODS: TMJs on one side in mice were subjected to partial discectomy. Both surgical and contralateral non-surgical TMJs were collected at 4, 8, 12 and 16 weeks post-surgery for histological examination. The morphology of the articular cartilage of the condyle was evaluated using a scoring system. RESULTS: A progression of articular cartilage degeneration was seen in the TMJs following unilateral partial discectomy, including increased proteoglycan staining in the extracellular matrix at 4 weeks, the appearance of chondrocyte clusters at 8 weeks, reduced proteoglycan staining and fibrillation at 12 weeks and the loss of articular cartilage at 16 weeks. In the contralateral non-surgical TMJs, increased proteoglycan staining occurred in the articular cartilage of the condyle at 8 weeks and continued to age. CONCLUSION: The result indicated that OA-like changes in one TMJ by partial discectomy could initiate early-onset articular cartilage degeneration in the contralateral non-surgical TMJ in mice.

Delayed progression of condylar cartilage degeneration, by reduction of the discoidin domain receptor 2, in the temporomandibular joints of osteoarthritic mouse models.

OBJECTIVE: To determine whether reduction of the discoidin domain receptor 2 (Ddr2) delays the progression of condylar cartilage degeneration in the temporomandibular joint (TMJ) of mouse models with osteoarthritis (OA). METHODS: Double-heterozygous (Col11a1- and Ddr2-haploinsufficiency, Col11a1(+/−);Ddr2(+/−)) mice were generated. TMJs of Ddr2(+/−) mice were subjected to partial discectomy. Condylar cartilage from the TMJ of Col11a1(+/−);Ddr2(+/−) mice, surgically treated (discectomy) Ddr2(+/−) mice, and their corresponding controls was characterized by means of histology and evaluated using a scoring system specific to mouse joints. RESULTS: The progression of condylar cartilage degeneration was significantly delayed in the TMJ of Col11a1(+/−);Ddr2(+/−) mice compared with those of the Col11a1(+/−) mice. The progression of condylar cartilage degeneration in the TMJ of Ddr2(+/−) mice following discectomy was also significantly delayed when compared with their wild-type littermates. CONCLUSION: Reduced expression of Ddr2 delays the progression of condylar cartilage degeneration, induced either by type XI collagen haploinsufficiency or by a partial discectomy, in TMJ.

Intact pericellular matrix of articular cartilage is required for unactivated discoidin domain receptor 2 in the mouse model.

Increased expression of the discoidin domain receptor 2 (DDR2) results from its interaction with collagen type II. This induces expression of matrix metalloproteinase (MMP)-13, leading to osteoarthritis (OA). To investigate the impact of the pericellular matrix of chondrocytes on DDR2, we generated a mouse model with inducible overexpression of DDR2 in cartilage. Conditional overexpression of DDR2 in mature mouse articular cartilage was controlled via the cartilage oligomeric matrix protein promoter using the Tet-Off-inducible system. Doxycycline was withdrawn at 1 month of age, and knee joints were examined at 2, 3, and 4 months of age. Microsurgery was performed on 3-month-old transgenic mice overexpressing DDR2 to destabilize the medial meniscus, and serial paraffin sections were examined at 2, 4, 8, and 12 weeks after surgery. DDR2 expression increased in the knee joints of transgenic mice. However, the increased DDR2 did not induce MMP-13 expression. No OA-like changes were observed in the transgenic mice at the age of 4 months. When transgenic mice were subjected to destabilizing of the medial meniscus, we observed accelerated progression to OA, which was associated with DDR2 activation. Therefore, conditionally overexpressing DDR2 in the mature articular cartilage of mouse knee joints requires activation to induce OA, and altered biomechanical stress can accelerate the onset of cartilage loss and progression to OA in transgenic mice.

Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice.

OBJECTIVE: To investigate whether the reduction of discoidin domain receptor 2 (DDR-2), a cell membrane tyrosine kinase receptor for native type II collagen, attenuates the progression of articular cartilage degeneration in mouse models of osteoarthritis (OA). METHODS: Double-heterozygous (type XI collagen-deficient [Col11a1(+/-)] and Ddr2-deficient [Ddr2(+/-)]) mutant mice were generated. Knee joints of Ddr2(+/-) mice were subjected to microsurgical destabilization of the medial meniscus. Conditions of the articular cartilage from the knee joints of the double-heterozygous mutant and surgically treated mice were examined by histology, evaluated using a modified Mankin scoring system, and characterized by immunohistochemistry. RESULTS: The rate of progressive degeneration in knee joints was dramatically reduced in the double-heterozygous mutant mice compared with that in the type XI collagen-deficient mice. The progression in the double-heterozygous mutant mice was delayed by ∼6 months. Following surgical destabilization of the medial meniscus, the progressive degeneration toward OA was dramatically delayed in the Ddr2(+/-) mice compared with that in their wild-type littermates. The articular cartilage damage present in the knee joints of the mice was directly correlated with the expression profiles of DDR-2 and matrix metalloproteinase 13. CONCLUSION: Reduction of DDR-2 expression attenuates the articular cartilage degeneration of knee joints induced either by type XI collagen deficiency or by surgical destabilization of the medial meniscus.

Oestrogen receptor beta mediates decreased occlusal loading induced inhibition of chondrocyte maturation in female mice.

OBJECTIVE: Temporomandibular joint (TMJ) disorders predominantly afflict women, suggesting that estrogen may play a role in the disease process. Defects in mechanical loading-induced TMJ remodelling are believed to be a major etiological factor in TMJ degenerative disease. Previously, we found that, decreased occlusal loading caused a significant decrease in early chondrocyte maturation markers (Sox9 and Col 2) in female, but not male, C57BL/6 wild type mice (1). The goal of this study was to examine the role of Estrogen Receptor (ER) beta in mediating these effects. DESIGN: 21-day-old male (n = 24) and female (n = 25) ER beta KO mice were exposed to decreased occlusal loading (soft diet administration and incisor trimming) for 4 weeks. At 49 days of age the mice were sacrificed. Proliferation, gene expression, Col 2 immunohistochemistry and micro-CT analysis were performed on the mandibular condyles. RESULTS: Decreased occlusal loading triggered similar effects in male and female ER beta KO mice; specifically, significant decreases in Col 10 expression, subchondral total volume, bone volume, and trabecular number. CONCLUSION: Decreased occlusal loading induced inhibition of chondrocyte maturation markers (Sox9 and Col 2) did not occur in female ER beta deficient mice.

Role of HTRA1, a serine protease, in the progression of articular cartilage degeneration.

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.