Mitogen-activated protein kinases (MAPKs) are ancient signal transducers well characterized as mediators of inflammation and neoplastic transformation. Recent work has expanded our understanding of their developmental functions, particularly in the regulation of bone mass via control of osteoblast differentiation. Here, we review the functions of MAPK pathways in osteoblasts, including a consideration of MAPK substrates. In particular, MAPKs function to regulate the key transcriptional mediators of osteoblast differentiation, with ERK and p38 MAPKs phosphorylating RUNX2, the master regulator of osteoblast differentiation. ERK also activates RSK2, which in turn phosphorylates ATF4, a transcriptional regulator of late-stage osteoblast synthetic functions. The MAP3Ks and MAP2Ks upstream of MAPKs have also been investigated, and significant differences have been found in the wiring of MAPK pathways in osteoblasts relative to other tissues. Thus, the investigation of MAPKs in osteoblasts has both revealed critical mechanisms for the maintenance of bone mass and added to our understanding of how the individual components of MAPK pathways function in concert in a complex in vivo system.

Mitogen-Activated Protein Kinase Pathways in Osteoblasts

Neurofibromatosis type 1 (NF1) is one of the most common inherited cancer syndromes in which affected individuals develop brain tumors.1 As such, children with NF1 are at risk for the formation of low-grade glial neoplasms involving the optic pathway (optic nerve, chiasm, and postchiasmal tracts; optic pathway glioma [OPG]),2,3 which can lead to visual impairment.4,5 Since surgery is not an option because of permanent nerve damage, and radiation therapy is associated with an increased incidence of fatal secondary high-grade glioma,6 the mainstay of treatment has been chemotherapy. For the past 25 years, the treatment of NF1-OPG has largely employed anti-neoplastic agents used for sporadic low-grade glioma7,8 with varying success.

Genetically engineered mouse (GEM) models provide unprecedented opportunities to identify and critically evaluate therapies specifically targeted to NF1-OPG. To this end, Nf1+/− mice with neuroglial progenitor Nf1 loss develop low-grade gliomas of the prechiasmatic optic nerves and chiasm with many similarities to their human counterparts.9,10 As observed in human NF1-OPG, these murine tumors harbor low proliferative indices, microglia infiltration, nuclear pleomorphism, cellular atypia, and bipolar neoplastic glial cells. Nf1 optic glioma mice have been previously employed to demonstrate that increased cell growth results from loss of Nf1 protein (neurofibromin) regulation of Ras in neuroglial progenitors, leading to elevated Ras and Ras pathway activation.11 The critical role of deregulated Ras signaling in Nf1 optic glioma formation is further underscored by the finding that Nf1+/− mice with constitutively active KRas expression in neuroglial progenitors develop optic glioma.12

Ras transmits its growth regulatory signal through downstream signaling intermediates, including protein kinase-B (Akt) and mitogen activated protein kinase (ERK). While previous studies from our laboratory have identified the Akt/mammalian target of rapamycin (mTOR) effector arm as a major regulator of Nf1 optic glioma growth,11,13 recent reports have demonstrated that ERK is the primary driver of tumor growth in other NF1-associated cancers.14,15 These observations have prompted recent clinical trials employing inhibitors of mitogen-activated protein kinase kinase (MEK) for the treatment of plexiform neurofibromas (NCT01362803) and brain tumors (NCT01885195) in individuals with NF1.

In this report, we sought to critically establish which Ras effector pathway is responsible for maintaining Nf1 optic glioma growth. Using a series of pharmacologic studies on Nf1-deficient astrocytes in vitro and Nf1 murine optic gliomas in vivo, we demonstrate that both phosphatidylinositol-3 kinase (PI3K)/Akt and MEK/ERK signaling pathways are responsible for neurofibromin regulation of mTOR activity, such that sustained inhibition of either PI3K or MEK activity suppresses Nf1 optic glioma proliferation and retinal ganglion cell (RGC) death in vivo. Together, these data provide further support for the use of agents that target mTOR as biologically based NF1-OPG treatments.

Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth.

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.

/pdf/valosin-containing-protein-and-neurofibromin-interact-to-3zzjqzbzpq.pdf

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

Oral health status is jeopardized in patients with neurofibromatosis (NF) type-1 (NF-1). The aim of the present study was to comprehensively review the oral manifestations in NF-1 patients. PubMed/Medline and Google-Scholar databases were explored using different keywords. Reviews, commentaries, letters to Editor and articles published in languages other than English were excluded. Results Neurofibromas of oral and perioral soft tissues with subsequent periodontitis, impacted and supernumerary teeth, enlarged alveolar process with dental spacing, morphological changes in teeth and class III molar relationship have been reported in NF-1 patients. Plexiform neurofibromas were reported both in oral soft tissue, maxilla and mandible with evidence of malignant transformation in some cases. Facial skeletal abnormalities, including enlargement of mandibular foramen, increased dimensions of the coronoid and sigmoid notches and notching of the posterior border of the mandible have also been reported. Association between dental caries and NF-1 remains unclear.

/pdf/oral-manifestations-in-patients-with-neurofibromatosis-type-4rrc0bzzjj.pdf

Oral manifestations in patients with neurofibromatosis type-1: a comprehensive literature review.

Background Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with various skeletal abnormalities occurring as part of a complex phenotype. Tibial dysplasia, which typically presents as anterolateral bowing of the leg with subsequent fracture and nonunion (pseudarthrosis), is a serious but infrequent osseous manifestation of NF1. Over the past several years, results from clinical and experimental studies have advanced our knowledge of the role of NF1 in bone. On the basis of current knowledge, we propose a number of concepts to consider as a theoretical approach to the optimal management of tibial pseudarthrosis. Methods A literature review for both clinical treatment and preclinical models for tibial dysplasia in NF1 was performed. Concepts were discussed and developed by experts who participated in the Children's Tumor Foundation sponsored International Bone Abnormalities Consortium meeting in 2011. Results Concepts for a theoretical approach to treating tibial pseudarthrosis include: bone fixation appropriate to achieve stability in any given case; debridement of the "fibrous pseudarthrosis tissue" between the bone segments associated with the pseudarthrosis; creating a healthy vascular bed for bone repair; promoting osteogenesis; controlling overactive bone resorption (catabolism); prevention of recurrence of the "fibrous pseudarthrosis tissue"; and achievement of long-term bone health to prevent recurrence. Conclusions Clinical trials are needed to assess effectiveness of the wide variation of surgical and pharmacologic approaches currently in practice for the treatment of tibial pseudarthrosis in NF1. Level of evidence Level V, expert opinion.

Approaches to treating NF1 tibial pseudarthrosis: consensus from the Children's Tumor Foundation NF1 Bone Abnormalities Consortium.

Skeletal abnormalities including scoliosis, tibial dysplasia, sphenoid wing dysplasia, and decreased bone mineral density (BMD) are associated with neurofibromatosis type 1 (NF1). We report the cellular phenotype of NF1 human-derived osteoclasts and compare the in vitro findings with the clinical phenotype. Functional characteristics (e.g., osteoclast formation, migration, adhesion, resorptive capacity) and cellular mechanistic alterations (e.g., F-actin polymerization, MAPK phosphorylation, RhoGTPase activity) from osteoclasts cultured from peripheral blood of individuals with NF1 (N = 75) were assessed. Osteoclast formation was compared to phenotypic, radiologic, and biochemical data. NF1 osteoprogenitor cells demonstrated increased osteoclast forming capacity. Human NF1-derived osteoclasts demonstrated increased migration, adhesion, and in vitro bone resorption. These activities coincided with increased actin belt formation and hyperactivity in MAPK and RhoGTPase pathways. Although osteoclast formation was increased, no direct correlation of osteoclast formation with BMD, markers of bone resorption, or the clinical skeletal phenotype was observed suggesting that osteoclast formation in vitro cannot directly predict NF1 skeletal phenotypes. While NF1 haploinsufficiency produces a generalized osteoclast gain-in-function and may contribute to increased bone resorption, reduced BMD, and focal skeletal defects associated with NF1, additional and perhaps local modifiers are likely required for the development of skeletal abnormalities in NF1.

/pdf/multiple-increased-osteoclast-functions-in-individuals-with-17yqd2cy58.pdf

Multiple Increased Osteoclast Functions in Individuals with Neurofibromatosis Type 1

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Multiple Increased Osteoclast Functions in Individuals with Neurofibromatosis Type 1