Mitogen-activated protein kinases as therapeutic targets in osteoarthritis

Loeser, Richard F.; Erickson, Elizabeth A.; Long, David

doi:10.1097/bor.0b013e3283090463

Cited by 118 publications

(115 citation statements)

References 46 publications

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“…Also noteworthy, the elevated, sustained levels of IGF-I produced in OA cartilage via rAAV might have been capable of counteracting the wellknown effects of pathogenic adipokines on the destruction of articular cartilage (3,4). Of further note, the activating effects of IGF-I via rAAV on the expression of its receptor in normal and OA cartilage were associated with significant increases in the expression of effectors of the IGF-IR signal transduction pathways (MAPK/ERK-1/2 and PI3K/Akt) and downstream transcription factors (Elk-1, SOX9) described for their impact on cell proliferation and survival and on the synthesis of extracellular cartilage matrix components (proteoglycans, type II collagen) (38,39,(77)(78)(79). These results are in good agreement with previous findings using recombinant .…”

Section: Discussionmentioning

confidence: 99%

“…We also analyzed the extent by which the candidate treatment with the rAAV-human IGF-I (rAAV-hIGF-I) vector was capable of durably restoring the structure of human OA cartilage vis-à-vis normal cartilage. Finally, we investigated the influence of rAAV-mediated IGF-I production upon the expression of key effectors of the IGF-I axis, specifically the IGF-binding proteins 3, 4 and 5 (IGFBP-3 to IGFBP-5) as well as the IGF-I receptor (IGF-IR) and downstream mitogenactivated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK-1/2) and phosphatidylinisitol-3/Akt (PI3K/Akt) signal transduction pathways (33)(34)(35)(36)(37)(38)(39), reported as being inhibitors (IGFBP3 and IGFBP4) (40)(41)(42) or potentiators (IGFBP5 and IGF-IR) (42,43) of the IGF-I actions during OA pathogenesis.…”

Section: Benefits Of Recombinant Adeno-associated Virus (Raav)-mediatmentioning

confidence: 99%

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Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

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Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of recombinant adeno-associated virus (rAAV)-mediated overexpression of human insulinlike growth factor (hIGF)-I to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival and anabolic effects of the rAAV-hIGF-I treatment in primary human normal and OA chondrocytes in vitro and in explant cultures in situ compared with control (reporter) vector delivery. Efficient, prolonged IGF-I secretion via rAAV stimulated the biological activities of OA chondrocytes in all the systems evaluated over extended periods of time, especially in situ, where it allowed for the long-term reconstruction of OA cartilage (at least for 90 d). Remarkably, production of high, stable amounts of IGF-I in OA cartilage using rAAV advantageously modulated the ex-

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Section: Discussionmentioning

confidence: 99%

Section: Benefits Of Recombinant Adeno-associated Virus (Raav)-mediatmentioning

confidence: 99%

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

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“…MAPKs are activated by extracellular stimuli and may play an important role in joint destruction by regulating the expression of proinflammatory cytokines and MMPs (31). To check the activity of "classical" MAPKs in ␤1-deficient AC chondrocytes, we performed IHC using antibodies that specifically recognize the phosphorylated forms of ERK-1/2, p38, and JNK.…”

Section: ␤1 Integrin Null Chondrocytes Display Normal Activation Of Mmentioning

confidence: 99%

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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“…However, ERK inhibitors have received little attention due to the potential toxicity of systemic ERK inhibition because the ERK-MAPK pathway is involved in a multitude of growth factor signaling pathways. Therefore, new strategies to inhibit the ERK-MAPK pathway such as non-ATP competitive inhibitors or inhibitors of downstream factors are needed (27).…”

Section: +mentioning

confidence: 99%

The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death

et al. 2009

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Abstract. In a screening program aimed at discovering anti-osteoarthritis (OA) drugs, we identified an imidazo [5,1-c] [1,4]thiazine derivative, ITZ-1, that suppressed both interleukin-1β (IL-1β)-induced proteoglycan and collagen release from bovine nasal cartilage in vitro and suppressed intra-articular infusion of IL-1β-induced cartilage proteoglycan degradation in rat knee joints. ITZ-1 did not inhibit enzyme activities of various matrix metalloproteinases (MMPs), which have pivotal roles in cartilage degradation, while it selectively inhibited IL-1β-induced production of MMP-13 in human articular chondrocytes (HAC). IL-1β-induced MMP production has been shown to be mediated by extracellular signal-regulated protein kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) family signal transduction molecules. An ERK-MAPK pathway inhibitor (U0126), but not a p38 kinase inhibitor (SB203580) or a JNK inhibitor (SP600125), also selectively inhibited IL-1β-induced MMP-13 production in HAC. Furthermore, ITZ-1 selectively inhibited IL-1β-induced ERK activation without affecting p38 kinase and JNK activation, which may account for its selective inhibition of MMP-13 production. Inhibition of nitric oxide (NO)-induced chondrocyte apoptosis has been another area of interest as a therapeutic strategy for OA, and ITZ-1 also suppressed NO-induced death in HAC. These results suggest that ITZ-1 is a promising lead compound for a disease modifying anti-OA drug program.

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Mitogen-activated protein kinases as therapeutic targets in osteoarthritis

Cited by 118 publications

References 46 publications

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death

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