Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway

Yasoda, Akihiro; Komatsu, Yasato; Chusho, Hideki; Miyazawa, Takashi; Ozasa, Ami; Miura, Masako; Kurihara, Tatsuya; Rogi, Tomohiro; Tanaka, Shoji; Suda, Michio; Tamura, Naohisa; Ogawa, Yoshihiro; Nakao, Kazuwa

doi:10.1038/nm971

Cited by 362 publications

(362 citation statements)

References 40 publications

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“…Interestingly, ERK1/2 MAP kinase activity is required for dephosphorylation of both p107 and p130, whereas p38 MAP kinase signaling is only necessary for dephosphorylation of p130 (Raucci et al, 2004). These data are in agreement with roles of both of these pathways in postmitotic chondrocytes (Zhen et al, 2000;Stanton et al, 2003;Murakami et al, 2004;Stanton et al, 2004;Yasoda et al, 2004). Furthermore, p107 dephosphorylation does not require transcription or translation, suggesting that it is independent of CKI induction, in contrast to p130 (Dailey et al, 2003).…”

Section: Function Of Cell-cycle Genes In the Growth Platesupporting

confidence: 74%

Cell‐cycle control and the cartilage growth plate

Beier

2004

Journal Cellular Physiology

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The longitudinal growth of endochondral bones is governed by proliferation and hypertrophic differentiation of growth plate chondrocytes. Numerous growth factors and hormones have been implicated in the regulation of these processes, but the intracellular mechanisms involved remain much less understood. We had suggested a role of cell-cycle genes in the integration of these diverse extracellular signals and their translation into coordinated proliferation and differentiation of chondrocytes. Numerous recent studies have provided support for such a scenario and provide novel insights into the regulation and function of cell-cycle genes in chondrocytes. This review article summarizes recent progress in the field.

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Section: Function Of Cell-cycle Genes In the Growth Platesupporting

confidence: 74%

Cell‐cycle control and the cartilage growth plate

Beier

2004

Journal Cellular Physiology

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“…We have previously reported that BNP-Tg mice with higher copy numbers of the transgene show marked skeletal overgrowth [47], indicating that BNP likely activates the physiological CNP/GC-B pathway in the bone to stimulate endochondral ossification [48]. Therefore, it is important to clarify whether the beneficial effects of BNP observed in this study are GC-A-dependent or GC-B-dependent.…”

Section: Discussionmentioning

confidence: 78%

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

et al. 2006

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Aims/hypothesis Brain natriuretic peptide (BNP) is a potent vasorelaxing and natriuretic peptide that is secreted from the heart and has cardioprotective properties. We have previously generated hypotensive transgenic mice (BNP-Tg mice) that overproduce BNP in the liver, which is released into the circulation. Using this animal model, we successfully demonstrated the amelioration of renal injury after renal ablation and in proliferative glomerulonephritis. Glomerular hyperfiltration is an early haemodynamic derangement, representing one of the key mechanisms of the pathogenesis of diabetic nephropathy. Based on the suggested involvement of increased endogenous natriuretic peptides, the aim of this study was to investigate their role in the development and progression of diabetic nephropathy. Materials and methods We evaluated the progression of renal injury and fibrogenesis in BNP-Tg mice with diabetes induced by streptozotocin. We also investigated the effect of BNP on high glucose-induced signalling abnormalities in mesangial cells. Results After induction of diabetes, control mice exhibited progressively increased urinary albumin excretion with impaired renal function, whereas these changes were significantly ameliorated in BNP-Tg mice. Notably, diabetic BNP-Tg mice revealed minimal mesangial fibrogenesis with virtually no glomerular hypertrophy. Glomerular upregulation of extracellular signal-regulated kinase, TGF-β and extracellular matrix proteins was also significantly inhibited in diabetic BNP-Tg mice. In cultured mesangial cells, activation of the above cascade under high glucose was abrogated by the addition of BNP. Conclusions/interpretation Chronic excess of BNP prevents glomerular injury in the setting of diabetes, suggesting that renoprotective effects of natriuretic peptides may be therapeutically applicable in preventing the progression of diabetic nephropathy.

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“…The anti-proliferative action of FGF 2 signaling in cartilage contrasts with the usual mitogenic response of cells to FGF stimulus (6), but the molecular basis of this paradox remains unclear. Recently, Erk MAP kinase was found as a candidate for FGFR3-mediated inhibition of chondrocyte proliferation and differentiation (7)(8)(9)(10).…”

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confidence: 99%

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Krejčı́

Masri

Salazar

et al. 2007

Journal of Biological Chemistry

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Activating mutations in fibroblast growth factor receptor 3 (FGFR3) cause several human dwarfisms characterized by diminished long bone growth (1). In cartilage, FGFR3 alters chondrocyte proliferation and differentiation by up-regulation of cell cycle inhibitors and stimulation of cartilage matrix degradation (2-5). The anti-proliferative action of FGF 2 signaling in cartilage contrasts with the usual mitogenic response of cells to FGF stimulus (6), but the molecular basis of this paradox remains unclear. Recently, Erk MAP kinase was found as a candidate for FGFR3-mediated inhibition of chondrocyte proliferation and differentiation (7-10).Protein kinase C (PKC) comprises a family of serine/threonine kinases that phosphorylate the consensus motif RXX(S/T)XR (11). The PKCs are further divided into three subfamilies based on sequence similarities and modes of activation. The conventional PKCs (PKC␣, -␤I, -␤II, and -␥) are activated by phosphatidylserine, diacylglycerol, and Ca 2ϩ , the novel PKCs (PKC␦, -⑀, -, and -) require only phosphatidylserine and diacylglycerol, and the atypical PKCs (aPKC; PKC and -) respond to phosphatidylserine alone (12). The PKC phosphorylation motif is present in many proteins (13), implicating PKCs as broad specificity protein kinases. PKCs are involved in numerous signaling events including activation of the Erk MAP kinase pathway. This is evident by potent Erk activation in cells treated with phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), which activates both conventional PKCs and novel PKCs through binding of their diacylglycerol site (14). In PMA-treated cells, PKCs target the Erk module at the level of both Raf-1 and MEK, through direct activatory phosphorylation or indirectly (15-21). Apart from PMA-mediated Erk activation, PKCs appear to be crucial for long term Erk activation by growth factors, including FGFs (20,[22][23][24][25], as well as for oncogenic .FGF signaling in chondrocytes leads to long term Ras/Erk activation, which appears to account for the growth inhibitory outcome of FGF treatment (8, 9). To date, little is known about chondrocyte properties of FGF signaling permitting prolonged Erk activity, although slow down-regulation of mutated FGFR3 appears to be involved (30,31).

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Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway

Cited by 362 publications

References 40 publications

Cell‐cycle control and the cartilage growth plate

Cell‐cycle control and the cartilage growth plate

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

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