Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments

Homandberg, Gene A.

doi:10.2741/a389

Cited by 96 publications

(106 citation statements)

References 46 publications

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“…35 In chondrocytes, the a5b1 integrin also binds proteolytic fragments of fibronectin, which have been shown to initiate a distinct signaling cascade with downstream effects that may lead to matrix degradation or remodeling. 36,37 Recent studies present evidence that a similar pathway may exist in disc, 38,39 and thus the a5b1 integrin may be a key receptor for cellmediated responses to matrix degradation in the IVD.…”

Section: Discussionmentioning

confidence: 99%

Functional integrin subunits regulating cell–matrix interactions in the intervertebral disc

Gilchrist

Chen

Richardson

et al. 2007

Journal Orthopaedic Research

109

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Cellular interactions with the extracellular matrix are key factors regulating cell survival, differentiation, and response to environmental stimuli in cartilagenous tissues. Much is known about the extracellular matrix proteins in the intervertebral disc (IVD) and their variations with region, age, or degenerative state of the tissue. In contrast, little is known of the integrin cell surface receptors that directly bind to and interact with these matrix proteins in the IVD. In almost all tissues, these integrin-mediated cell-matrix interactions are important for transducing environmental cues arising from mechanical stimuli, matrix degradation fragments, and cytokines into intracellular signals. In this study, cells from the nucleus pulposus and anulus fibrosus regions of porcine IVDs were analyzed via flow cytometry to quantify integrin expression levels upon isolation and after monolayer culture. Assays of cell attachment to collagens, fibronectin, and laminin were performed after functional blocking of select integrin subunits to evaluate the role of specific integrins in cell attachment. In situ distribution and co-localization of integrins and laminin were also characterized. Results identify integrin receptors critical for IVD cell interactions with collagens (a1b1) and fibronectin (a5b1). Additionally, dramatic differences in cell-laminin interactions were observed between cells of the nucleus and anulus regions, including differences in a6 integrin expression, cell adhesion to laminin, and in situ pericellular environments. These findings suggest laminin-cell interactions may be important and unique to the nucleus pulposus region of the IVD. The results of this study provide new information on functional cell-matrix interactions in tissues of the IVD. ß

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Section: Discussionmentioning

confidence: 99%

Functional integrin subunits regulating cell–matrix interactions in the intervertebral disc

Gilchrist

Chen

Richardson

et al. 2007

Journal Orthopaedic Research

109

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“…We and others have observed enhanced expression of FN and OPN mRNA in human OA-affected cartilage compared with normal cartilage (M. G. Attur, M. N. Dave, S. A. Stuchin, A. S. Kowalski, C. A. Lopez, J. Zhang, S. B. Abramson, D. T. Denhardt, and A. R. Amin, manuscript in preparation) (5,6). These ECM proteins may alter chondrocyte functions; FN and FN fragments have been reported to induce IL-1␤, IL-6, GM-CSF, matrix metalloproteinases (MMPs), and proteoglycan release in chondrocytes (5,6).…”

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confidence: 99%

“…These ECM proteins may alter chondrocyte functions; FN and FN fragments have been reported to induce IL-1␤, IL-6, GM-CSF, matrix metalloproteinases (MMPs), and proteoglycan release in chondrocytes (5,6). Engagement of ␣ 5 ␤ 1 integrin by FN has also been implicated in chondrocyte adhesion, spreading, and proliferation in vitro (7,8).…”

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confidence: 99%

Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by α5β1 and αVβ3 Integrins

Attur

Dave

Clancy

et al. 2000

The Journal of Immunology

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Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin (FN) and osteopontin (OPN) mRNA in differential display and bioinformatics screen. Functional genomic analysis shows that the engagement of the integrin receptors α5β1 and αvβ3 of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of α5β1 using activating mAb JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE2 as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by α5β1 integrin ligation is mediated via induction and autocrine production of IL-1β, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, αvβ3 complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1β, NO, and PGE2 (triggered by α5β1, IL-1β, IL-18, or IL-1β, TNF-α, plus LPS) in a dominant negative fashion by osteoarthritis-affected cartilage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated “outside in” and “inside out” signaling very likely influences cartilage homeostasis, and its deregulation may play a role in the pathogenesis of osteoarthritis.

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“…This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5). The autocrine production of IL-1 in OA-affected cartilage is amplified by engagement of integrins such as ␣ 5 ␤ 1 by abnormally expressed extracellular matrix proteins, including proteolytic fragments of fibronectin (5,6).…”

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confidence: 99%

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

Attur¹,

Dave²,

Cipolletta³

et al. 2000

Journal of Biological Chemistry

118

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Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1␤-induced nitric oxide (NO) and/or prostaglandin E 2 production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC 50 for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1␤ mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance. Osteoarthritis (OA)1 is considered a non-inflammatory arthritis, characterized by a limited infiltration of neutrophils into the synovial space and, in general, an absence of the classical signs of inflammation. Chondrocytes embedded within articular cartilage that is avascular and aneural reside in a sequestered environment, perhaps more than other cell types, whereby cellular metabolism is regulated by an autocrine mechanism responsive to biomechanical and pericellular signals. Recent observations by this and other laboratories indicate that, despite the general absence of clinical signs of inflammation, chondrocytes derived from patients with OA, show superinduction of proinflammatory genes typically associated with the products of synovial tissues in rheumatoid arthritis, including nitric-oxide synthase, cyclooxygenase-2, TNF␣, IL-6, and IL-8. The spontaneous production of the corresponding gene products and inflammatory mediators promotes a catabolic state, which leads to progressive cartilage damage in OA (1-4). This intraarticular inflammatory response in OA-affected cartilage, which may be considered as an in situ "molecular inflammation," is partially dependent on autocrine IL-1␤ production, which induces and sustains an imbalance of cartilage homeostasis and extracellular matrix synthesis (5). The autocrine production of IL-1 in OA-affected cartilage is amplified by engagement of integrins such as ␣ 5 ␤ 1 by abnormally expressed extracellular matrix proteins, including proteolytic fragments of fibronectin (5, 6)...

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Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments

Cited by 96 publications

References 46 publications

Functional integrin subunits regulating cell–matrix interactions in the intervertebral disc

Functional integrin subunits regulating cell–matrix interactions in the intervertebral disc

Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by α5β1 and αVβ3 Integrins

Reversal of Autocrine and Paracrine Effects of Interleukin 1 (IL-1) in Human Arthritis by Type II IL-1 Decoy Receptor

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