Pathogenesis of osteoarthritis‐like changes in the joints of mice deficient in type IX collagen

Hu, Kejia; Xu, Lin; Cao, Lina; Flahiff, Charlene; Brussiau, J.; Ho, K. K. Y.; Setton, Lori A.; Youn, Inchan; Guilak, Farshid; Olsen, Bjørn R.; Li, Yefu

doi:10.1002/art.22040

Cited by 126 publications

(113 citation statements)

References 39 publications

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“…In contrast to the TSP-null mouse strains, previous studies of type IX collagen knockout mice showed earlyonset osteoarthritis, 31,43 less MATN3 incorporation into 46 and slower fracture repair. 47 We observed similar findings and, in addition, found wider growth plates and significant limb shortening at 1 month of age.…”

Section: Discussionmentioning

confidence: 61%

Skeletal Abnormalities in Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, and Type IX Collagen

Posey¹,

Hankenson

Veerisetty³

et al. 2008

The American Journal of Pathology

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Thrombospondin-5 (TSP5) is a large extracellular matrix glycoprotein found in musculoskeletal tissues. TSP5 mutations cause two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia; both show a characteristic growth plate phenotype with retention of TSP5, type IX collagen (Col9), and matrillin-3 in the rough endoplasmic reticulum. Whereas most studies focus on defining the disease process, few functional studies have been performed. TSP5 knockout mice have no obvious skeletal abnormalities, suggesting that TSP5 is not essential in the growth plate and/or that other TSPs may compensate. In contrast, Col9 knockout mice have diminished matrillin-3 levels in the extracellular matrix and earlyonset osteoarthritis. To define the roles of TSP1, TSP3, TSP5, and Col9 in the growth plate, all knockout and combinatorial strains were analyzed using histomorphometric techniques. While significant alterations in growth plate organization were found in certain single knockout mouse strains, skeletal growth was only mildly disturbed. In contrast, dramatic changes in growth plate organization in TSP3/5/Col9 knockout mice resulted in a 20% reduction in limb length, corresponding to similar short stature in humans. These studies show that type IX collagen may regulate growth plate width; TSP3, TSP5, and Col9 appear to contribute to growth plate organization; and TSP1 may help define the Thrombospondin-5 (TSP5), also known as cartilage oligomeric matrix protein, is the fifth member of the TSP gene family that includes trimeric (TSP1 and TSP2) and pentameric (TSP3, TSP4, and TSP5) protein members. 1First identified in cartilage and considered to be cartilage specific, TSP5 was subsequently found in other musculoskeletal tissues and is used as a marker for osteoarthritis and joint injury.2-9 TSP5 has been intensely studied, because mutations in this gene were shown to cause pseudoachondroplasia and multiple epiphyseal dysplasia (MED/EDM1). 10 -17 Mutations result in a dominantnegative effect on TSP5 causing massive retention of mutant TSP5 and other extracellular matrix (ECM) proteins, including types II and IX collagen and matrillin-3 (MATN3), in large rough endoplasmic reticulum cis-ternae. 15,18 -20 Recent studies show that these ECM proteins associate with TSP5 to form a structured intracellular matrix network. 20 Interestingly, mutations in MATN3 (MED/EDM5) and all three type IX collagen (Col9) genes also cause MED phenotypes (MED/EDM2, -3, and -6) that are typically milder than the MED condition caused by TSP5 mutations. 21Different approaches have attempted to define the role of TSP5. Recent work suggests that TSP5 stimulates chondrocyte proliferation through the binding of granulinepithelin precursor, an autocrine growth factor. 22 Binding experiments demonstrate that TSP5 interacts with types I,

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Section: Discussionmentioning

confidence: 61%

Skeletal Abnormalities in Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, and Type IX Collagen

Posey¹,

Hankenson

Veerisetty³

et al. 2008

The American Journal of Pathology

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“…Existing spontaneous mouse models of OA are commonly limited by the time to develop a full phenotype. For example, STR/ORT (39), collagen type IX (COL9A1)-deficient, and heterozygous Col11a1 chondrodysplasia mice each take >6 mo to develop robust disease, although subtle changes are present in the latter two models at 3 mo of age (31,40). Mice lacking NFATc2 alone develop OA, although also with slow kinetics.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of Col2a1, a major organic component of cartilage matrix, was also up-regulated, suggesting that cartilage matrix turnover is hyperdynamic, perhaps in an effort to compensate for catabolism. Absence of type IX collagen in Col9a1 −/− mice results in age-dependent OA-like changes in mice, and Col9a1 expression was moderately reduced in Nfatc1 col2 Nfatc2 −/− mice (31). Inducible deletion of sex-determining region Y (SRY)-Box 9 (Sox9) in adult mice is associated with proteoglycan depletion at articular surfaces, and Sox9 expression was also reduced (32).…”

Section: Molecular Characterization Of Cartilage Matrix Degradation Inmentioning

confidence: 99%

NFATc1 and NFATc2 repress spontaneous osteoarthritis

Greenblatt

Ritter²,

Wright

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Osteoarthritis (OA) was once viewed originally as a mechanical disease of "wear and tear," but advances made during the past two decades suggest that abnormal biomechanics contribute to active dysregulation of chondrocyte biology, leading to catabolism of the cartilage matrix. A number of signaling and transcriptional mechanisms have been studied in relation to the regulation of this catabolic program, but how they specifically regulate the initiation or progression of the disease is poorly understood. Here, we demonstrate that cartilage-specific ablation of Nuclear factor of activated T cells c1 (Nfatc1) in Nfatc2 −/− mice leads to early onset, aggressive OA affecting multiple joints. This model recapitulates features of human OA, including loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and eventual progression to cartilage effacement and joint instability. Consistent with the notion that NFATC1 is an OA-suppressor gene, NFATC1 expression was significantly down-regulated in paired lesional vs. macroscopically normal cartilage samples from OA patients. The highly penetrant, early onset, and severe nature of this model make it an attractive platform for the preclinical development of treatments to alter the course of OA. Furthermore, these findings indicate that NFATs are key suppressors of OA, and regulating NFATs or their transcriptional targets in chondrocytes may lead to novel disease-modifying OA therapies.

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“…Genotyping procedures of Col9a1 -/-and cho/+ mice have been described previously (8,10). Col9a1 -/-, cho/+ and wild-type mice were separated and maintained under a 12-hour lighting schedule (12 hours with light and 12 hours without light).…”

Section: Genotyping Of Col9a1 -/-And Cho/+ Micementioning

confidence: 99%

“…It has been reported that the expression of MMP-3 and MMP-13 is increased in TM joints of OA patients (4,5). We have been investigating the pathogenesis of OA using two murine mutant models: type IX collagen-deficient (Col9a1 -/-) and type XI collagen-haploinsufficient (heterozygous chondrodysplasia, cho/+) mice (6)(7)(8). Both mutant mouse strains developed normally, but exhibited age-dependent OA-like changes in knee and TM joints starting at 3 months of age.…”

Section: Introductionmentioning

confidence: 99%

Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice

Lam¹,

Li²,

Waldman³

et al. 2007

Archives of Oral Biology

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Our previous studies demonstrated that mutations in type IX and type XI collagens in mice caused osteoarthritis (OA)-like changes in knee and temporomandibular (TM) joints. We also found that the overexpression of matrix metalloproteinase 13 (Mmp-13) was probably due to the upregulation of a collagen receptor, discoidin domain receptor 2 (Ddr2), which was responsible for knee cartilage degeneration in mutant mice. The objective of our study was to determine whether the expression of Mmp-3, Mmp-13 and Ddr2 was increased in OA-like TM joints in mutant mice using immunohistochemistry. We found that the staining for Ddr2, Mmp-13 and Mmp-derived type II collagen fragments in tissue sections from 6 month-old mice was increased in TM joints of the mutant mice. In contrast, we found no difference in the staining for Mmp-3 amongst the two mutant mice and their wild-type littermates. We conclude that, similar to previous observations in knee joints, the overexpression of Ddr2 and Mmp-13 may be responsible for the OA-like change in TM joints in mutant mice.

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Pathogenesis of osteoarthritis‐like changes in the joints of mice deficient in type IX collagen

Cited by 126 publications

References 39 publications

Skeletal Abnormalities in Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, and Type IX Collagen

Skeletal Abnormalities in Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, and Type IX Collagen

NFATc1 and NFATc2 repress spontaneous osteoarthritis

Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice

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