Loss of α10β1 integrin expression leads to moderate dysfunction of growth plate chondrocytes

Bengtsson, Tommy; Aszódi, Attila; Nicolae, Claudia M.; Hunziker, Ernst B.; Lundgren-Åkerlund, Evy; Fässler, Reinhard

doi:10.1242/jcs.01678

Cited by 131 publications

(109 citation statements)

References 18 publications

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Section: Chondrocytes Of the Articular Cartilage (Ac)supporting

confidence: 57%

“…In addition, the cartilage matrix shows a sparse, distorted collagen network. Similar, but milder abnormalities were found in mice lacking the collagen-binding integrin ␣10␤1 or integrin-linked kinase in cartilage (11,12).Although these works have identified ␤1 integrins as essential regulators of growth plate development, the role of integrins in joint morphogenesis, adult joint function, and pathology is incompletely understood. In the embryonic mouse limb culture system, administration of ␤1 and ␣5 blocking antibodies or RGD peptides induced ectopic joint formation between proliferating and hypertrophic chondrocytes of the growth plate, suggesting that ␣5␤1 integrin controls the decision…”

mentioning

confidence: 84%

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β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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The lack of ␤1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of ␤1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the ␤1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to ␤1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. ␤1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of ␤1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways. Chondrocytes of the articular cartilage (AC)2 secrete a unique set of extracellular matrix (ECM) molecules that assemble into interactive associates composed of collagens, proteoglycans (PGs), and non-collagenous glycoproteins (1). The fibrillar collagen meshwork supplies cartilage with its tensile strength, whereas the hydrated glycosaminoglycan (GAG) chains of PGs (mainly aggrecan) generate an osmotic swelling pressure that resists compressive forces. In diarthrodial joints, the molecular composition and the physical properties of the cartilage are principal determinants for the shock-absorbing function of articular surfaces upon mechanical loading. During the development of osteoarthritis (OA), an imbalance between anabolic and catabolic processes increases the proteolysis of PGs and collagens (2, 3), which eventually leads to the mechanical weakening of the AC and culminates in its progressive destruction. Physiological and pathological remodeling of the AC ECM is primarily attributed to the activities of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like repeat (ADAMTS) proteases (4, 5) and is controlled by the communication between the cells and their environment.An increasing amount of evidence suggests that interactions between chondrocytes and the ECM through the integrin family of heterodimeric (␣␤) transmembrane receptors play a central role in cartilage function (6). Int...

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Section: Chondrocytes Of the Articular Cartilage (Ac)supporting

confidence: 57%

mentioning

confidence: 84%

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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“…This finding also implies that type I and type II collagens, which seem to promote mineralization, are unlikely to use the α 1 β 1 receptor to mediate these effects, but rather, they may utilize other integrin combinations, such as α 2 β 1 , α 10 β 1 or the DDRs. In favor of this generalization, deficiencies in α 10 , β 1 , or DDR2 have been shown to hinder chondrocyte maturation and matrix mineralization in calcifying bones, [147][148][149] although it is not known whether similar mechanisms are at play in vascular calcification.…”

Section: Atherosclerotic Calcificationmentioning

confidence: 99%

Collagens in the progression and complications of atherosclerosis

et al. 2009

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Collagens constitute a major portion of the extracellular matrix in the atherosclerotic plaque, where they contribute to the strength and integrity of the fibrous cap, and also modulate cellular responses via specific receptors and signaling pathways. This review focuses on the diverse roles that collagens play in atherosclerosis; regulating the infiltration and differentiation of smooth muscle cells and macrophages; controlling matrix remodeling through feedback signaling to proteinases; and influencing the development of atherosclerotic complications such as plaque rupture, aneurysm formation and calcification. Expanding our understanding of the pathways involved in cell-matrix interactions will provide new therapeutic targets and strategies for the diagnosis and treatment of atherosclerosis.

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“…Regarding the role of collagen-binding integrins the knockout phenotypes of mice deficient in integrin a10 and a11, respectively, have now been published [6,45] and interestingly the enigmatic DDR collagen receptors have recently been shown to affect the function of collagen-binding integrins [1,53,62]. In coming years we are likely to learn more about the cross-talk of collagen-binding integrins with other receptor groups.…”

Section: What Has Beenmentioning

confidence: 99%

I Domain Integrins

2014

Advances in Experimental Medicine and Biology

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Loss of α10β1 integrin expression leads to moderate dysfunction of growth plate chondrocytes

Cited by 131 publications

References 18 publications

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Collagens in the progression and complications of atherosclerosis

I Domain Integrins

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