FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Reinhold, Martina I.; Abe, Makoto; Kapadia, Ravi M.; Liao, Zhixiang; Naski, Michael C.

doi:10.1074/jbc.m404855200

Cited by 72 publications

(60 citation statements)

References 61 publications

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“…There is a paucity of data regarding the effect of Cn on chondrogenesis and chondrocyte metabolism (22)(23)(24)(25). One study showed that the NF-AT transcription factor, NF-ATp, which is the downstream target of Cn, is a repressor of chondrogenesis (22).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

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Objective. To determine whether intracellular calcineurin (Cn), a calcium-activated phosphatase, regulates the anabolic and catabolic activities of chondrocytes, and is a potential target in the treatment of osteoarthritis (OA).Methods. CnA expression was examined in cartilage tissue samples and cultured chondrocytes from OA patients, using immunohistochemistry and Western blot analysis, respectively. Concentrations of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the culture supernatants were determined using enzyme-linked immunosorbent assay. Levels of nitric oxide (NO) and type II collagen (CII) were measured using the Griess reaction and Western blot analysis, respectively. In addition, the pathologic role of Cn was examined in an in vivo model in which experimental OA was induced in mice by injecting type VII collagenase into the knee joints.Results. CnA was highly expressed in the chondrocytes of lesional OA cartilage. Cyclosporin A (CSA), a Cn inhibitor, inhibited spontaneous and interleukin-1␤-stimulated production of NO, MMP-1, and MMP-3 in chondrocytes. However, CSA increased the levels of production of CII, TIMP-1, and transforming growth factor ␤. Similar changes in MMP-1, NO, and CII expression levels in chondrocytes were observed after the targeted inhibition of Cn by overexpression of calcineurin binding protein 1, a natural Cn antagonist. Moreover, in the mouse model, animals treated with CSA showed a significant decrease in both the extent and the severity of cartilage damage, which were assessed macroscopically and microscopically, compared with vehicle-treated animals.Conclusion. These results suggest that CnA is critically involved in the catabolic and anabolic activities of chondrocytes as well as in the progression of experimental OA. Targeted inhibition of CnA may be an effective treatment strategy for OA.The failure of chondrocytes to maintain cartilage integrity is a key event leading to joint destruction in many arthritic conditions, including rheumatoid arthritis (RA), osteoarthritis (OA), and septic arthritis (1,2). Chondrocytes respond to a variety of stimuli, including proinflammatory cytokines and mechanical loading, by increasing the concentration of cartilage degradative enzymes and catabolic mediators. A disturbance in the regulation of the anabolic and catabolic activities of chondrocytes can result in a net loss of cartilage matrix components. Regardless of the initiating stimuli, the key process in cartilage degradation is similar, involving specific matrix metalloproteinases (MMPs), nitric oxide (NO), and aggrecanases, which are members of the ADAMTS family (3). Previous studies have demonstrated that interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) also play key roles in cartilage degradation by stimulating their own production and inducing chondrocytes to produce MMPs and NO (4,5).

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Section: Discussionmentioning

confidence: 99%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

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“…Interestingly, FGF-18 has been suggested to facilitate the chondrogenic activity of bone morphogenetic proteins (BMPs), well-known anabolic factors, by suppressing the expression of noggin, a naturally occurring inhibitor of BMP signaling (Reinhold et al, 2004). Noggin expression may play a vital role in helping to explain the opposite roles of FGF-18 and bFGF in human cartilage.…”

Section: Fgf-18 (A) Fgf-18 In Articular Cartilagementioning

confidence: 99%

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

Ellman

Muddasani

et al. 2008

Gene

152

131

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“…Mechanistically, FGF2 enhances canonical BMP2 signaling in osteoblasts through promoting nuclear localization of RUNX2 and phospho-SMAD1/5/8 ). Moreover, FGF2 isoforms specifically modulate BMP2 function and osteoblast differentiation , and FGF2, FGF9, and FGF18 inhibit the expression of the BMP antagonist Noggin in vitro and in vivo Reinhold et al 2004;Fakhry et al 2005). Thus, multiple mechanisms mediate FGF and BMP signaling interactions, leading to regulation of osteoblast differentiation.…”

Section: Intramembranous Mesenchymal Condensationsmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Cited by 72 publications

References 61 publications

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

Fibroblast growth factor signaling in skeletal development and disease

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