Bone resorption in syndromes of the Ras/MAPK pathway

Stevenson, David A.; Schwarz, Elisabeth L.; Carey, John C.; Viskochil, David; Hanson, Heather; Bauer, Sonja; Weng, Hsin-Yi; Greene, Tom; Reinker, Kent A.; Swensen, Jeffrey; Chan, Rebecca J.; Yang, Feng-Chun; Senbanjo, Linda T.; Yang, Zhiyuan; Mao, Rong; Pasquali, Marzia

doi:10.1111/j.1399-0004.2010.01619.x

Cited by 86 publications

(91 citation statements)

References 53 publications

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“…Osteoclastogenesis can be activated by RAS signaling, such as occurs in Nf1 deficiency (5,11,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). We observed a gain in the number of osteoclasts at the Nf1-null murine fracture site, in agreement with previous studies (51)(52)(53)(54)(55)(56)(57).…”

Section: Discussionsupporting

confidence: 91%

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

et al. 2016

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Tibial pseudarthrosis causes substantial morbidity in patients with neurofibromatosis type 1 (NF1). We studied tibial pseudarthrosis tissue from patients with NF1 and found elevated levels of b-catenin compared to unaffected bone. To elucidate the role of b-catenin in fracture healing, we used a surgically induced tibial fracture model in conditional knockout (KO) Nfl (Nf1 flox/flox ) mice. When treated with a Cre-expressing adenovirus (Ad-Cre), there was a localized knockdown of Nf1 in the healing fracture and a subsequent development of a fibrous pseudarthrosis. Consistent with human data, elevated b-catenin levels were found in the murine fracture sites. The increased fibrous tissue at the fracture site was rescued by local treatment with a Wingless-type MMTV integration site (Wnt) antagonist, Dickkopf-1 (Dkk1). The murine pseudarthrosis phenotype was also rescued by conditional b-catenin gene inactivation. The number of colony-forming unit osteoblasts (CFU-Os), a surrogate marker of undifferentiated mesenchymal cells able to differentiate to osteoblasts, correlated with the capacity to form bone at the fracture site. Our findings indicate that the protein level of b-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of b-catenin in NF1 causes a shift away from osteoblastic differentiation resulting in a pseudarthrosis in vivo. These results support the notion that pharmacological modulation of b-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. b-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications. FASEB J. 30, 3227-3237 (2016). www.fasebj.orgNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by activated RAS signaling and mutations that dysregulate the NF1 protein (neurofibromin). NF1-related skeletal abnormalities are an important cause of morbidity with osteoporosis, scoliosis, and tibial dysplasia affecting more than half of affected individuals. Tibial dysplasia typically starts with anterolateral tibial bowing, characteristically progressing to a fracture that will not heal, termed a pseudarthrosis. Normal fracture healing is characterized by the deposition of new bone from osteoblasts, followed by a period of remodeling in which osteoclasts are active. At the tibial pseudarthrosis fracture site, however, is fibrous hamartoma tissue contain cells that do not undergo osteoblastic differentiation form. There is also an increase in osteoclastogenic activity at the fracture site, when compared to the healing in a normal fractured tibia (1-4). Because tibial pseudarthrosis is refractive to medical treatment, the only management options are surgical. For those continuing to experience chronic pain and impaired mobility, an amputation may be required if other treatments are not effective.Germline heterozygous mutations of NF1 cause NF1. In some but not all NF1-related tibial pseudarthrosis, a second hit to the NF1 gen...

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Section: Discussionsupporting

confidence: 91%

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

et al. 2016

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“…15). In cardio-facio-cutaneous syndrome, MEK1 and MEK2 mutations within the negative regulatory helix result in a constitutively activated form of MEK (33)(34)(35). In a MEK1 mutagenesis screen, MEK1 Q56P , among others, conferred resistance to MEK and BRAF inhibitors (25).…”

Section: And Mek1mentioning

confidence: 99%

Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated byNRASorMEKMutations

Greger

Eastman

Zhang

et al. 2012

Molecular Cancer Therapeutics

319

261

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Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF V600E and the YUSIT1 BRAF V600K melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib).

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“…It is also known that neurofibromin regulates the functions of osteoclast (14,15) and skeletal muscle development (16). Although the Ras/MAPK pathway, the downstream signaling of neurofibromin, has been implicated in bone resorption (17), the detailed mechanism underlying the bony defects in patients with NF1 remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Wang¹,

Shih²,

Chen³

et al. 2011

J. Clin. Invest.

104

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Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1 +/-mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.

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Bone resorption in syndromes of the Ras/MAPK pathway

Cited by 86 publications

References 53 publications

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated byNRASorMEKMutations

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

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