Matrilin-3 Is Dispensable for Mouse Skeletal Growth and Development

Conclusion. Aberrant expression and processing of MATN3 are hallmarks of conventional cartilaginous neoplasms. A particular step in the maturation of MATN3 limits its processing through the secretion machinery, resulting in its intracellular accumulation upon increased expression. Soluble, secreted MATN3, however, down-regulates SOX9 at the messenger RNA and protein levels. The first EGF-like domain of MATN3 is a critical determinant of its regulatory activity toward SOX9. These activities of MATN3 suggest that its increased expression in osteoarthritis might contribute to the degeneration of articular cartilage.Articular cartilage is mostly made of extracellular specialized collagens and proteoglycans, with physical properties that support frictionless movements and the load-bearing capacity of the joints. Homeostasis of carti-

“…It should be noted, however, that an independently constructed mouse model of MATN3 knockout was not found to exhibit any detectable phenotype (11).…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Increased expression of matrilin‐3 not only in osteoarthritic articular cartilage but also in cartilage‐forming tumors, and down‐regulation of SOX9 via epidermal growth factor domain 1–dependent signaling

Vincourt¹,

Vignaud²,

Lionneton³

et al. 2008

“…COMPdeficient mice are indistinguishable from their wild-type littermates and display no obvious defects in skeletal development (18). Matrilin 3-knockout mice show only minor changes (19,20), having wider collagen fibrils and an increased cartilage collagen volume density, but no up-regulation of other matrilin family members is observed.…”

mentioning

confidence: 97%

“…Despite the large number of studies on matrilins and COMP, their roles in the function, assembly, and remodeling of the cartilage extracellular matrix are not fully understood. To shed light on their in vivo function, both COMP-null (18) and matrilin 3-null (19,20) mice were generated. COMPdeficient mice are indistinguishable from their wild-type littermates and display no obvious defects in skeletal development (18).…”

mentioning

confidence: 99%

Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double‐deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

Groma¹,

Xin²,

Grskovic³

et al. 2012

Self Cite

Objective. Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.Methods. To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.Results. At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)-deficient mice.Conclusion. We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 doubledeficient and MMP-13-deficient mice.The 2 major components of the cartilage extracellular matrix are the fibrillar collagens and the large hyaluronan-binding proteoglycan aggrecan. A variety of different proteins, including cartilage oligomeric matrix protein (COMP) and matrilin 3, modulate the assembly and structure of the extracellular matrix, generating complex functional networks. Matrilins are noncollagenous oligomeric extracellular matrix proteins with similar domain structure and function. Matrilin 1 and matrilin 3 are found almost exclusively in cartilage, while matrilin 2 and matrilin 4 have a broader tissue distribution. Subunits of matrilins 1 and 4 mainly form homotrimers, whereas subunits of matrilins 2 and 3 are found in homotetramers (1,2). In addition, heterotrimers consisting of matrilin 1 and matrilin 3 subunits can form. Matrilins function as adaptor proteins in the extracellular matrix and connect collagen fibrils with each other and with aggrecan (2). Via their von Willebrand type A-like domain, matrilins interact with several other matrix components, including COMP (3),

Combined role of type IX collagen and cartilage oligomeric matrix protein in cartilage matrix assembly: Cartilage oligomeric matrix protein counteracts type IX collagen–induced limitation of cartilage collagen fibril growth in mouse chondrocyte cultures

Blumbach¹,

Bastiaansen-Jenniskens²,

DeGroot³

et al. 2009

Objective. Defects in the assembly and composition of cartilage extracellular matrix are likely to result in impaired matrix integrity and increased susceptibility to cartilage degeneration. The aim of this study was to determine the functional interaction of the collagen fibril-associated proteins type IX collagen and cartilage oligomeric matrix protein (COMP) during cartilage matrix formation.Methods. Primary chondrocytes from mice deficient in type IX collagen and COMP (double-deficient) were cultured in monolayer or alginate beads. Anchorage of matrix proteins, proteoglycan and collagen content, collagen crosslinks, matrix metalloproteinase activity, and mechanical properties of the matrix were measured. Electron microscopy was used to study the formation of fibrillar structures.Results. In cartilage lacking both type IX collagen and COMP, matrilin 3 showed decreased matrix anchorage. Less matrilin 3 was deposited in the matrix of double-deficient chondrocytes, while larger amounts were secreted into the medium. Proteoglycans were less well retained in the matrix formed in alginate cultures, while collagen deposition was not significantly affected. Electron microscopy revealed similar cartilage collagen fibril diameters in the cultures of double-deficient and wild-type chondrocytes. In contrast, a larger fibril diameter was observed in the matrix of chondrocytes deficient in only type IX collagen. Conclusion. Our results show that type IX collagen and COMP are involved in matrix assembly by mediating the anchorage and regulating the distribution of other matrix macromolecules such as proteoglycans and matrilins and have counteracting effects on collagen fibril growth. Loss of type IX collagen and COMP leads to matrix aberrations that may make cartilage more susceptible to degeneration.