A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis

El-Hoss, Jad; Cheng, Tegan L.; Carpenter, Eleanor Clare; Sullivan, Kate; Deo, Nikita; Mikulec, Kathy; Little, David; Schindeler, Aaron

doi:10.2106/jbjs.m.00862

Cited by 23 publications

(22 citation statements)

References 41 publications

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“…Fractures were generated in 8‐wk‐old male Sprague‐Dawley rats weighing ~250‐300 g. Rats were anesthetized with 0.3% pentobarbital sodium (Sigma‐Aldrich) intraperitoneally at 30 mg/kg body weight. The fracture model was established as previously described (38, 59, 60). An intramedullary needle (1.2‐mm diameter stainless steel syringe needle) was inserted inside the medullary canal of the tibia for fixation.…”

Section: Methodsmentioning

confidence: 99%

IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cellsviaWnt/β‐catenin signaling pathway

Zhang

Chen

et al. 2018

FASEB j.

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Insulin-like growth factor-binding protein 7 (IGFBP7), a low-affinity IGF binder, may play an important role in bone metabolism. However, its function in osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs) remains unclear. Therefore, we investigated its effects on osteogenic differentiation. Overexpression of IGFBP7 enhanced the expression of osteo-specific genes and proteins, and IGFBP7 knockdown decreased osteogenesis-specific markers. More mineral deposits and higher alkaline phosphatase activity were observed after the up-regulation of IGFBP7. Moreover, β-catenin levels were up-regulated by the overexpression of IGFBP7 or the addition of extracellular IGFBP7 protein and were reduced by the depletion of IGFBP7. The increase in osteogenic differentiation due to the overexpression of IGFBP7 was partially decreased by specific Wnt/β-catenin signaling inhibitors. Using a rat tibial osteotomy model, a sheet of IGFBP7-overexpressing BMSCs improved bone healing, as demonstrated by imaging, biomechanical, and histologic analyses. Taken together, these findings indicate that IGFBP7 regulates the osteogenic differentiation of BMSCs partly via the Wnt/β-catenin signaling pathway.-Zhang, W., Chen, E., Chen, M., Ye, C., Qi, Y., Ding, Q., Li, H., Xue, D., Gao, X., Pan, Z. IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/β-catenin signaling pathway.

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Section: Methodsmentioning

confidence: 99%

IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cellsviaWnt/β‐catenin signaling pathway

Zhang

Chen

et al. 2018

FASEB j.

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“…Nf1 null fractures feature abundant fibrous tissue at the callus site that is associated with poor bone healing (Fig. A) . Fibrosis and cartilage were analyzed quantitatively on histological sections stained with Picrosirius Red and Alcian Blue.…”

Section: Resultsmentioning

confidence: 99%

“…Local application of purified recombinant Ad‐Cre virus to induce a tibial knockout was provided in a variation of the previously published technique where virus was dripped to saturate an absorbable collagen sponge (ACS, Medtronic Australasia) from an rhBMP‐2 implant kit. Ad‐Cre virus was produced and purified in house as previously described with 1 × 10 8 infectious units of purified virus applied to the ACS that was implanted at the fracture site at the time of surgery . 10 μg lyophilized rhBMP‐2 (Medtronic) reconstituted in sterile water was co‐administered via the ACS.…”

Section: Methodsmentioning

confidence: 99%

“…In 2014, this Nf1 null mouse fracture model was used to test two interventions: Systemic MEK inhibitor PD0325901 and/or local delivery of rhBMP-2. 10 Biologically, the NF1 gene product neurofibromin is a negative regular of Ras and reduced function enhances Ras-MEK-MAPK signaling. 11 In Nf1 null fractures, both targeted inhibition of MEK and local rhBMP-2 administration led to increased callus bone volume.…”

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confidence: 99%

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Improved union and bone strength in a mouse model of NF1 pseudarthrosis treated with recombinant human bone morphogenetic protein‐2 and zoledronic acid

Deo

Cheng

Mikulec

et al. 2017

Journal Orthopaedic Research

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Tibial pseudarthrosis associated with Neurofibromatosis type 1 (NF1) is an orthopedic condition with consistently poor clinical outcomes. Using a murine model that features localized double inactivation of the Nf1 gene in an experimental tibial fracture, we tested the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and/or the bisphosphonate zoledronic acid (ZA). Tibiae were harvested at 3 weeks for analysis, at which time there was negligible healing in un-treated control fractures (7% union). In contrast, rhBMP-2 and rhBMP-2/ZA groups showed significantly greater union (87% and 93%, p < 0.01 for both). Treatment with rhBMP-2 led to a 12-fold increase in callus bone volume and this was further increased in the rhBMP-2/ZA group. Mechanical testing of the healed rhBMP-2 and rhBMP-2/ZA fractures showed that the latter group had significantly higher mechanical strength and was restored to that of the un-fractured contralateral leg. Co-treatment with rhBMP-2/ZA also reduced fibrous tissue infiltration at the fracture site compared to rhBMP alone (p = 0.068). These data support the future clinical investigation of this combination of anabolic and anti-resorptive agents for the treatment of NF1 pseudarthrosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:930-936, 2018.

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“…Several other MEK inhibitors such as cobimetinib (melanoma and pancreatic cancer) [144,145], PD0325901 [146,147], pimasertib (lung, colorectal cancer, pancreatic adenocarcinoma, melanoma and multiple myeloma) [148], binimetinib (MEK162, ARRY-162, ARRY-438162) (melanoma) and refametinib (hepatocellular carcinoma) [149,150] are ongoing in clinical trials for the treatment of different cancers.…”

Section: Selumetinibmentioning

confidence: 99%

Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances

Hojjat‐Farsangi

2015

Journal of Drug Targeting

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Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.

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A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis

Abstract: This study examines a signaling pathway-based approach to treating poor bone healing in a model of NF1 pseudarthrosis.

Cited by 23 publications

References 41 publications

IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cellsviaWnt/β‐catenin signaling pathway

IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cellsviaWnt/β‐catenin signaling pathway

Improved union and bone strength in a mouse model of NF1 pseudarthrosis treated with recombinant human bone morphogenetic protein‐2 and zoledronic acid

Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances

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