Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis

Inoue, Tomoyuki; Boyle, David L.; Corr, Maripat; Hammaker, Deepa; Davis, Roger J.; Flavell, Richard A.; Firestein, Gary S.

doi:10.1073/pnas.0509188103

Cited by 96 publications

(86 citation statements)

References 36 publications

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“…This is consistent with the well-documented activation of MAPK families in human RA (27)(28)(29)(30). Thus, even in the preclinical disease phase, the joints of the HuTNF-Tg mice showed an activation of these 2 MAPK members, suggesting that p38 MAPK and ERK mediate the cellular effects of TNF right from the start of molecular onset of arthritis.…”

Section: Discussionsupporting

confidence: 87%

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis

Hayer¹,

Redlich²,

Korb³

et al. 2007

Arthritis & Rheumatism

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Objective. To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis.Methods. Human tumor necrosis factor (TNF)-transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease.Results. Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus-like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up-regulation of interleukin-1 (IL-1) and IL-6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis.Conclusion. Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.

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Section: Discussionsupporting

confidence: 87%

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis

Hayer¹,

Redlich²,

Korb³

et al. 2007

Arthritis & Rheumatism

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“…Mice lacking MKK3, one of the upstream kinases, which activate p38 MAPK, are protected from arthritis induced by transfer of serum from K/BxN mice. The phenotype was associated with strong inhibition of p38 phosphorylation and decreased IL-1␤ production in the inflamed joints (31). Similarly, deletion of the downstream kinase MAPKAP2, one of the best characterized substrates of p38MAPK, protected mice against collagen-induced arthritis.…”

Section: Discussionmentioning

confidence: 92%

“…Importantly, genetic deletion of MAPK kinase (MKK)3, an upstream activator of p38 MAPKs, or of MAPK-activated protein (MAPKAP)2, a downstream effector of p38 MAPKs, has shown to confer protection from arthritis (31,32). Thus, it is particularly important to understand the respective role of the various p38 MAPK isoforms on the course of inflammatory arthritis.…”

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confidence: 99%

The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

Böhm

Hayer

Kilian

et al. 2009

The Journal of Immunology

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Pharmacological inhibitors have provided evidence for the key role of p38 MAPK in osteoclast differentiation and in inflammation-induced bone loss. However, these inhibitors block more than one of the four p38 isoforms, usually p38α and p38β, and sometimes also other kinases such as JNK3. We show in this study that p38α is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38α as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-α. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38α were protected against TNF-α-induced bone destruction at the site of inflammation as well as against TNF-α-mediated systemic bone loss. The bone protection was associated to decreased osteoclast numbers in vivo as well as a decreased IL-1β expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38α-deficient cells, knockdown of p38α in monocytes resulted in a decreased osteoclast differentiation in vitro. It was not caused by major changes in RANKL-mediated ERK or JNK activation but rather associated to an increased NF-κB activation caused by a decrease in IκBα recovery. Thus, our data show that developing specific inhibitors of the α-isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis.

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“…Of these two kinases, MKK3 appears to be the most attractive target for studies of genetic deletion, because MKK3-p38 signalling has been shown to be nonredundant in some pathological processes [30,31]. Furthermore, mouse studies have shown that Mkk3 deficiency is protective in models of passive arthritis and streptozotocin-induced pancreatic inflammation [32,33]. In the current study, Mkk3-deficient db/db mice were created and used to examine the role of MKK3-p38 signalling in the development of obesity, hyperglycaemia and nephropathy in the db/db model of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

et al. 2008

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Aims/hypothesis Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. Methods Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. Results Mkk3+/+ db/db and Mkk3 −/− db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 +/+ db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 −/− db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 −/− db/ db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 −/− db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. Conclusions/interpretation MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.

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Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis

Cited by 96 publications

References 36 publications

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis

The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

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