Abnormal collagen fibrils in tendons of biglycan/fibromodulin‐deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis

Ameye, Laurent; Aria, Dean; Jepsen, Karl J.; Oldberg, Åke; Xu, T.; Young, Marian F.

doi:10.1096/fj.01-0848com

Cited by 317 publications

(289 citation statements)

References 29 publications

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“…Even though decorin and biglycan are often found in different regions of the extracellular matrix and respond differently to growth factors [4], biglycan competes with decorin for the same binding site on type I collagen fibrils [4]. Thus, compensatory behavior of biglycan has been reported in Dcn −/− cell-seeded collagen gels and native tissues [16,34,35].…”

Section: Discussionmentioning

confidence: 99%

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

et al. 2008

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Cyclic strain evokes the expression of the small leucine-rich proteoglycans decorin and biglycan in 2-D cultures and native tissues. However, strain dependent expression of these proteoglycans has not been demonstrated in engineered tissues. We hypothesized that the absence of decorin may compromise the effect of cyclic strain on the development of engineered tissues. Thus, we investigated the contribution of decorin to tissue organization in cyclically-strained collagen gels relative to statically-cultured controls. Decorin null (Dcn −/− ) and wild-type murine embryonic fibroblasts were seeded within collagen gels and mechanically conditioned using a Flexcell ® Tissue Train ® culture system. After eight days, the cyclically-strained samples demonstrated greater collagen fibril density, proteoglycan content, and material strength for both cell types. On the other hand, increases in cell density, collagen fibril diameter, and biglycan expression were observed only in the cyclically-strained gels seeded with Dcn −/− cells. Although cyclic strain caused an elevation in proteoglycan expression regardless of cell type, the type of proteoglycan differed between groups: the Dcn −/− cell-seeded gels produced an excess of biglycan not found in the wild-type controls. These results suggest that decorin-mediated tissue organization is strongly dependent upon tissue type and mechanical environment.

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Section: Discussionmentioning

confidence: 99%

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

et al. 2008

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“…Mice were genotyped as described in ref. 26. KAT-4 anaplastic thyroid carcinoma cells (5 ϫ 10 6 ) or rat PROb (5 ϫ 10 6 ) colorectal cells were injected s.c. in the left flank of the mice and treated with Fc:T␤RII (10 mg/kg) as described in refs.…”

Section: Methodsmentioning

confidence: 99%

“…Fibromodulin controls collagen matrix structure in tendons and ligaments, and deficient mice show altered tissue organization with fewer and structurally abnormal collagen fiber bundles. The collagen fibrils are thinner (23), tendons and ligaments have reduced tensile strength, and the animals develop knee-joint instability and osteoarthritis (24)(25)(26). Fibromodulin mRNA has been detected in a variety of clinical malignancies, such as lung, breast, and prostate carcinomas (27)(28)(29).…”

mentioning

confidence: 99%

Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma

Oldberg¹,

Kalamajski²,

Salnikov

et al. 2007

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

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Research on the biology of the tumor stroma has the potential to lead to development of more effective treatment regimes enhancing the efficacy of drug-based treatment of solid malignancies. Tumor stroma is characterized by distorted blood vessels and activated connective tissue cells producing a collagen-rich matrix, which is accompanied by elevated interstitial fluid pressure (IFP), indicating a transport barrier between tumor tissue and blood. Here, we show that the collagen-binding proteoglycan fibromodulin controls stroma structure and fluid balance in experimental carcinoma. Gene ablation or inhibition of expression by antiinflammatory agents showed that fibromodulin promoted the formation of a dense stroma and an elevated IFP. Fibromodulindeficiency did not affect vasculature but increased the extracellular fluid volume and lowered IFP. Our data suggest that fibromodulin controls stroma matrix structure that in turn modulates fluid convection inside and out of the stroma. This finding is particularly important in relation to the demonstration that targeted modulations of the fluid balance in carcinoma can increase the response to cancer therapeutic agents.physiology ͉ TGF-␤ ͉ tumor physiology ͉ inflammation ͉ interstitial fluid pressure

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“…14 Additionally, modifications in ECM collagens, such as type VI and type X⌱ collagens, 15,16 and small ECM proteoglycans, such as asporin, biglycan, and fibromodulin, [17][18][19] can lead to the development of OA in the TMJ and in other joints. Furthermore, studies have reported that humans with genetic diseases involving defects in cartilage-related ECM genes, such as Marfan syndrome 20 and Ehlers-Danlos syndrome, 21 experience TMJ dysfunction.…”

Section: Fmodmentioning

confidence: 99%

“…18,19 Functionally, SLRPs can control ECM structure by interacting with the network of cartilage proteins and can mediate cell metabolism by binding to members of the transforming growth factor ␤ superfamily (TGF-␤). 17,23,24 Bgn and Fmod both bind to TGF-␤1, 23 a potent growth factor that regulates the formation and degradation of the ECM and maintains cartilage integrity in murine and human articular cartilage.…”

Section: Fmodmentioning

confidence: 99%

Biglycan and Fibromodulin Have Essential Roles in Regulating Chondrogenesis and Extracellular Matrix Turnover in Temporomandibular Joint Osteoarthritis

Embree

Kilts

Ono

et al. 2010

The American Journal of Pathology

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103

110

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The temporomandibular joint is critical for jaw movements and allows for mastication, digestion of food, and speech. Temporomandibular joint osteoarthritis is a degenerative disease that is marked by permanent cartilage destruction and loss of extracellular matrix (ECM). To understand how the ECM regulates mandibular condylar chondrocyte (MCC) differentiation and function, we used a genetic mouse model of temporomandibular joint osteoarthritis that is deficient in two ECM proteins, biglycan and fibromodulin (Bgn Fmod؊/؊ ). Given the unavailability of cell lines, we first isolated primary MCCs and found that they were phenotypically unique from hyaline articular chondrocytes isolated from the knee joint. Using Bgn Fmod؊/؊ MCCs, we discovered the early basis for temporomandibular joint osteoarthritis arises from abnormal and accelerated chondrogenesis. Transforming growth factor (TGF)-␤1 is a growth factor that is critical for chondrogenesis and binds to both biglycan and fibromodulin. Our studies revealed the sequestration of TGF-␤1 was decreased within the ECM of Bgn ؊/0 Fmod ؊/؊ MCCs, leading to overactive TGF-␤1 signal transduction. Using an explant culture system, we found that overactive TGF-␤1 signals induced chondrogenesis and ECM turnover in this model. We demonstrated for the first time a comprehensive study revealing the importance of the ECM in maintaining the mandibular condylar cartilage integrity and identified biglycan and fibromodulin as novel key players in regulating chondrogenesis and ECM turnover during temoporomandibular joint osteoarthritis pathology.

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Abnormal collagen fibrils in tendons of biglycan/fibromodulin‐deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis

Cited by 317 publications

References 29 publications

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma

Biglycan and Fibromodulin Have Essential Roles in Regulating Chondrogenesis and Extracellular Matrix Turnover in Temporomandibular Joint Osteoarthritis

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