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Biomedical subjects

Georg Schett

Publications and source records attributed to Georg Schett.

At least 19 recordsLinked to original sources
PubMed2007

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

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.

Animals↗
PubMed2007

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis.

OBJECTIVE: Imatinib mesylate is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc). METHODS: The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin-induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo. RESULTS: Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGFbeta and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. CONCLUSION: These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

Aged↗
PubMed2006

Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction.

OBJECTIVE: To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed. METHODS: Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed. RESULTS: Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors. CONCLUSION: These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.

Animals↗
PubMed2006

Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis.

OBJECTIVE: Activation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (alpha, beta, gamma, and delta), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease. METHODS: Studies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the alpha, beta, gamma, and delta isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry. RESULTS: Immunoblot analysis revealed that alpha and gamma were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cell-specific markers revealed that macrophages expressed the alpha and gamma isoforms, synovial fibroblasts the beta and gamma isoforms, and granulocytes the delta isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double-labeling with isoform-specific antibody and pan-p38 antibody against the phosphorylated form of p38 MAPK showed activation of the alpha and gamma isoforms. Occasional activation of the beta isoform was also noted in the synovial lining and the endothelium, whereas the delta isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPKalpha and -gamma but not p38 MAPKbeta or -delta. CONCLUSION: These data show that the alpha and gamma isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.

Adult↗
PubMed2006

Rheumatoid arthritis: inflammation and bone loss.

Chronic synovial inflammation is usually accompanied by bone erosion. Due to resulting structural damage, bone erosion is a major reason for disability in RA patients. Anti-rheumatic drug therapy is focussed not only on the control of synovial inflammation but also on preserving bone from structural damage. Bone erosion in arthritis is a consequence of synovial osteoclast formation. Therapeutic approaches which interfere with synovial osteoclastogenesis and/or osteoclast activation are therefore of great interest. This review describes the mechanism of inflammatory bone loss, describes its cellular and molecular players and gives insights in current therapeutic tools to inhibit this process.

Animals↗
PubMed2006

Imbalance of local bone metabolism in inflammatory arthritis and its reversal upon tumor necrosis factor blockade: direct analysis of bone turnover in murine arthritis.

Chronic arthritis typically leads to loss of periarticular bone, which results from an imbalance between bone formation and bone resorption. Recent research has focused on the role of osteoclastogenesis and bone resorption in arthritis. Bone resorption cannot be observed isolated, however, since it is closely linked to bone formation and altered bone formation may also affect inflammatory bone loss. To simultaneously assess bone resorption and bone formation in inflammatory arthritis, we developed a histological technique that allows visualization of osteoblast function by in-situ hybridization for osteocalcin and osteoclast function by histochemistry for tartrate-resistant acid phosphatase. Paw sections from human tumor necrosis factor transgenic mice, which develop an erosive arthritis, were analyzed at three different skeletal sites: subchondral bone erosions, adjacent cortical bone channels, and endosteal regions distant from bone erosions. In subchondral bone erosions, osteoclasts were far more common than osteoblasts. In contrast, cortical bone channels underneath subchondral bone erosions showed an accumulation of osteoclasts but also of functional osteoblasts resembling a status of high bone turnover. In contrast, more distant skeletal sites showed only very low bone turnover with few scattered osteoclasts and osteoblasts. Within subchondral bone erosions, osteoclasts populated the subchondral as well as the inner wall, whereas osteoblasts were almost exclusively found along the cortical surface. Blockade of tumor necrosis factor reversed the negative balance of bone turnover, leading to a reduction of osteoclast numbers and enhanced osteoblast numbers, whereas the blockade of osteoclastogenesis by osteoprotegerin also abrogated the osteoblastic response. These data indicate that bone resorption dominates at skeletal sites close to synovial inflammatory tissue, whereas bone formation is induced at more distant sites attempting to counter-regulate bone resorption.

Animals↗
PubMed2006

The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease.

Owing to the common coincidence of osteoporosis and vascular disease, pathophysiological links between both disorders have long been sought. The osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/receptor activator of NF-kappaB ligand (RANKL) cytokine network, a key regulatory system in bone homeostasis, has been implicated recently in vascular calcification, changes in matrix composition and diabetic macroangiopathy, aortic aneurysm development, heart failure and, most importantly, advanced atherosclerosis, plaque destabilization and manifestation of cardiovascular diseases. The concept of an active role of RANKL and OPG in vascular pathophysiology is intriguing and is gaining increasing support from both epidemiological and basic research. OPG serum level is considered to be a stable and reliable indicator of the overall activity of the OPG/RANK/RANKL axis and may find application as a biomarker of vascular risk and prognosis. RANKL in turn may be a suitable target for novel therapies. Pharmacological strategies for specific interference with the OPG/RANK/RANKL axis are currently being developed and evaluated in osteoporosis therapy.

Biomarkers↗
PubMed2005

Aberrant expression of the autoantigen heterogeneous nuclear ribonucleoprotein-A2 (RA33) and spontaneous formation of rheumatoid arthritis-associated anti-RA33 autoantibodies in TNF-alpha transgenic mice.

Human TNF-alpha transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, >50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.

Animals↗
PubMed2005

The binding of sera of patients with SLE to bacterial and mammalian DNA.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antibodies to DNA (anti-DNA). Although these antibodies have features of antigen drive, the source of this DNA is not defined. To assess the potential role of foreign and self-DNA as driving antigens, the specificity of SLE sera for bacterial and mammalian DNA was evaluated. Micrococcus lysodeikticus (MC) and calf thymus (CT) DNA were tested as antigens, with absorption on CT DNA columns used to identify antibodies to antigenic sites on the two DNA. Among 9 sets of longitudinal sera tested, all showed binding to both DNA, and none showed exclusive or predominant binding to CT DNA. With absorbed sera, antibodies could be distinguished in terms of cross-reactive or selective binding to the DNAs. These findings suggest that anti-DNA antibodies vary in specificity and are consistent with a role of both foreign and self-DNA in anti-DNA induction.

Adolescent↗
PubMed2005

Association of serum-soluble heat shock protein 60 with carotid atherosclerosis: clinical significance determined in a follow-up study.

BACKGROUND AND PURPOSE: Previous work has shown that soluble heat shock protein 60 (HSP60; sHSP60), present in circulating blood, is associated with carotid atherosclerosis. In the current evaluation, we tested the hypothesis that sHSP60 levels are associated with the progression of carotid arteriosclerosis, prospectively. METHODS: The association of sHSP60 with early atherogenesis (5-year development and progression of nonstenotic carotid plaques) was investigated as part of the population-based prospective Bruneck Study. The current study focused on the follow-up period between 1995 and 2000 and, thus, included 684 subjects. RESULTS: sHSP60 levels measured in 1995 and 2000 were highly correlated (r=0.40; P<0.001), indicating consistency over a 5-year period. Circulating HSP60 levels were significantly correlated with antilipopolysaccharide and anti-HSP60 antibodies. It was also elevated in subjects with chronic infection (top quintile group of HSP60, among subjects with and without chronic infection: 23.8% versus 17.0%; P=0.003 after adjustment for age and sex). HSP60 levels were significantly associated with early atherogenesis, both in the entire population (multivariate odds ratio, for a comparison between quintile group V versus I+II: 2.0 [1.2 to 3.5] and the subgroup free of atherosclerosis at the 1995 baseline: 3.8 [1.6 to 8.9]). The risk of early atherogenesis was additionally amplified when high-sHSP60 and chronic infection were present together. CONCLUSIONS: Our study provides the first prospective data confirming an association between high levels of sHSP60 and early carotid atherosclerosis. This possibly indicates an involvement of sHSP60 in activating proinflammatory processes associated with early vessel pathology.

Autoantigens↗
PubMed2005

Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption.

Heme oxygenase 1 (HO-1) plays an important role in vascular disease, transplantation, and inflammation. In animal models of acute and chronic inflammation, induction of HO-1 has anti-inflammatory and cytoprotective properties. Since inflammation is an important trigger of osteoclastogenesis, we hypothesized that HO-1 might influence osteoclastogenesis. We investigated the effects of induction of HO-1 on osteoclast formation in vitro and in vivo. Furthermore, we addressed the role of HO-1 in inflammatory bone loss in humans. When HO-1 was induced by hemin in vitro, a significant dose-dependent inhibition of osteoclastogenesis was observed. Up-regulation of HO-1 was mediated by activation of MAPK and primarily prevented differentiation of osteoclast precursors to osteoclasts, whereas it did not affect mature osteoclasts. Anti-osteoclastogenic properties of hemin were based on a down-regulation of c-fms, RANK, TRAF-6, and c-fos. In addition, induction of HO-1 inhibited TNF-triggered osteoclast differentiation in vitro as well as LPS-driven inflammatory bone loss in vivo. Furthermore, HO-1 induction suppressed osteoclastogenesis and bone destruction in a TNF-mediated arthritis. In line, assessment of synovial tissue from rheumatoid arthritis patients revealed that osteoclasts are usually HO-1 negative. Moreover, serum levels of bilirubin, a metabolite of HO-1, were elevated in rheumatoid arthritis patients without bone damage, suggesting HO-1 affects bone loss in humans. In summary, these data indicate that HO-1 negatively regulates osteoclastogenesis, leading to a positive net balance of bone.

Animals↗
PubMed2005

Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis.

Rheumatoid arthritis (RA) leads to destruction of cartilage and bone. Whether rheumatoid arthritis also affects the adjacent bone marrow is less clear. In this study, we investigated subcortical bone marrow changes in joints from patients with RA. We describe penetration of the cortical barrier by synovial inflammatory tissue, invasion into the bone marrow cavity and formation of mononuclear cell aggregates with B cells as the predominant cell phenotype. B cells expressed common B cell markers, such as CD20, CD45RA, and CD79a, and were mature B cells, as indicated by CD27 expression. Plasma cells were also present and were enriched in the regions between aggregates and inflammatory tissue. Moreover, molecules for B cell chemoattraction, such as BCA-1 and CCL-21, homing, mucosal addressin cell adhesion molecule-1 and survival, BAFF, were expressed. Endosteal bone next to subcortical bone marrow aggregates showed an accumulation of osteoblasts and osteoid deposition. In summary, we show that synovial inflammatory tissue can reach the adjacent bone marrow by fully breaking the cortical barrier, which results in formation of B cell-rich aggregates as well as increased formation of new bone. This suggests that bone marrow is an additional compartment in the disease process of RA.

Aged↗
PubMed2005

Tumour necrosis factor activates the mitogen-activated protein kinases p38alpha and ERK in the synovial membrane in vivo.

Tumour necrosis factor (TNF) is considered to be a major factor in chronic synovial inflammation and is an inducer of mitogen-activated protein kinase (MAPK) signalling. In the present study we investigated the ability of TNF to activate MAPKs in the synovial membrane in vivo. We studied human TNF transgenic mice--an in vivo model of TNF-induced arthritis--to examine phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) and p38MAPKalpha in the inflamed joints by means of immunoblot and immunohistochemistry. In addition, the effects of systemic blockade of TNF, IL-1 and receptor activator of nuclear factor-kappaB (RANK) ligand on the activation of MAPKs were assessed. In vivo, overexpression of TNF induced activation of p38MAPKalpha and ERK in the synovial membrane, whereas activation of JNK was less pronounced and rarely observed on immunohistochemical analysis. Activated p38MAPKalpha was predominantly found in synovial macrophages, whereas ERK activation was present in both synovial macrophages and fibroblasts. T and B lymphocytes did not exhibit major activation of any of the three MAPKs. Systemic blockade of TNF reduced activation of p38MAPKalpha and ERK, whereas inhibition of IL-1 only affected p38MAPKalpha and blockade of RANK ligand did not result in any decrease in MAPK activation in the synovial membrane. These data indicate that TNF preferentially activates p38MAPKalpha and ERK in synovial membrane exposed to TNF. This not only suggests that targeted inhibition of p38MAPKalpha and ERK is a feasible strategy for blocking TNF-mediated effects on joints, but it also shows that even currently available methods to block TNF effectively reduce activation of these two MAPKs.

Animals↗
PubMed2005

RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis.

UNLABELLED: RANKL is an essential mediator of bone erosions, but the role of RANKL in systemic bone loss had not been studied in arthritis. RANKL protein was increased in rat joint extracts and serum at the earliest stages of arthritis. Osteoprotegerin (OPG) treatment reversed local and systemic bone loss, suggesting that RANKL is both a marker and mediator of bone loss in arthritis. INTRODUCTION: RANKL is well established as an essential mediator of bone erosions in inflammatory arthritis, but the role of RANKL in systemic bone loss in arthritis had not been studied. We hypothesized that serum RANKL could serve as both a mediator and as a novel biomarker for local and systemic bone loss in arthritis. We challenged this hypothesis in two established rat models of inflammatory arthritis. We sought to determine whether serum RANKL was elevated early in disease progression and whether RANKL suppression could prevent both local and systemic bone loss in these models. MATERIALS AND METHODS: Detailed time-course studies were conducted in animals with collagen-induced (CIA) or adjuvant-induced (AIA) arthritis to evaluate the onset and progression of inflammation (paw swelling), bone erosions, osteoclast numbers, and RANKL protein levels in arthritic joints and in serum. Additional CIA and AIA rats (n=8/group) received placebo (PBS) or recombinant OPG (3 mg/kg three times weekly) for 10 days beginning 4 days after disease onset (first macroscopic evidence of hind paw erythema and edema) to assess the role of RANKL in local and systemic bone loss. RESULTS: RANKL protein was significantly elevated in the joints and serum of CIA and AIA rats within 1-2 days of disease onset. Increased RANKL levels were associated with local (hind paw) and systemic (vertebral) osteopenia in both models. The RANKL inhibitor OPG prevented local and systemic osteopenia in both models of established disease. CONCLUSIONS: RANKL protein is significantly increased both locally and systemically during the earliest stages of inflammatory arthritis in rats, suggesting that serum RANKL might have prognostic value for bone erosions and systemic osteopenia in this condition. RANKL inhibition through OPG prevented local and systemic bone loss in these arthritis models, suggesting that RANKL inhibition is a promising new approach for treating bone loss in arthritis.

Animals↗
PubMed2005

I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss.

Transcription factor, nuclear factor kappaB (NF-kappaB), is required for osteoclast formation in vivo and mice lacking both of the NF-kappaB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IkappaB kinase (IKK) complex that mediate NF-kappaB activation, IKKalpha and IKKbeta, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKbeta subunit as a transducer of signals from receptor activator of NF-kappaB (RANK) to NF-kappaB. Although IKKalpha is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKbeta is required for osteoclastogenesis in vitro and in vivo. IKKbeta also protects osteoclasts and their progenitors from tumor necrosis factor alpha-induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

Animals↗
PubMed2005

CD44 is a determinant of inflammatory bone loss.

Chronic inflammation is a major trigger of local and systemic bone loss. Disintegration of cell-matrix interaction is a prerequisite for the invasion of inflammatory tissue into bone. CD44 is a type I transmembrane glycoprotein that connects a variety of extracellular matrix proteins to the cell surface. Tumor necrosis factor (TNF) is a major inducer of chronic inflammation and its overexpression leads to chronic inflammatory arthritis. By generating CD44(-/-) human TNF-transgenic (hTNFtg) mice, we show that destruction of joints and progressive crippling is far more severe in hTNFtg mice lacking CD44, which also develop severe generalized osteopenia. Mutant mice exhibit an increased bone resorption due to enhanced number, size, and resorptive capacity of osteoclasts, whereas bone formation and osteoblast differentiation are not affected. Responsiveness of CD44-deficient osteoclasts toward TNF is enhanced and associated with increased activation of the p38 mitogen-activated protein kinase. These data identify CD44 as a critical inhibitor of TNF-driven joint destruction and inflammatory bone loss.

Animals↗
PubMed2005

The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis.

Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-kappaB, Akt and Jnk. Inactivation of the gene encoding Gab2 in mice results in osteopetrosis and decreased bone resorption as a result of defective osteoclast differentiation. We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis.

Adaptor Proteins, Signal Transducing↗