Distal tibial fracture repair in a neurofibromatosis type 1-deficient mouse treated with recombinant bone morphogenetic protein and a bisphosphonate

Birke, Oliver; Yu, Na; Morse, Alyson; Ruys, Andrew J.; Baldock, Paul A.; Little, David

doi:10.1302/0301-620x.93b8.25940

Cited by 38 publications

(34 citation statements)

References 37 publications

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“…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). In vitro studies have shown a biphasic effect of b-catenin on osteoclast proliferation and differentiation (58).…”

Section: Discussionsupporting

confidence: 92%

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: 92%

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

et al. 2016

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“…Bone morphogenic proteins (BMPs) are known for their ability to promote osteoprogenitor differentiation 39 but had limited effect on the differentiation of Nf1 +/− osteoprogenitors and on bone union in Nf1 +/− mice 40,41 . Recombinant hBMP2 (100 ng.ml −1 ) was unable to stimulate ALP activity, nor the formation of CFU–Ob in BMSC cultures from Col2-Nf1 KO mice, although it did, as expected, promote CFU–Ob formation and ALP activity in WT BMSC cultures, following 2 weeks of treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Ndong¹,

Makowski

Uppuganti³

et al. 2014

Nat Med

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Mineralization of the skeleton depends on the balance between levels of pyrophosphate (PPi), an inhibitor of hydroxyapatite formation, and phosphate generated from PPi breakdown by alkaline phosphatase (ALP). We report here that ablation of Nf1, encoding the RAS/GTPase–activating protein neurofibromin, in bone–forming cells leads to supraphysiologic PPi accumulation, caused by a chronic ERK–dependent increase in genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank. It also prevents BMP2–induced osteoprogenitor differentiation and, consequently, expression of ALP and PPi breakdown, further contributing to PPi accumulation. The short stature, impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts could be corrected by enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization, suggest that altered PPi homeostasis contributes to the skeletal dysplasiae associated with neurofibromatosis type-1 (NF1), and that some of the NF1 skeletal conditions might be preventable pharmacologically.

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“…Some experimental in vitro and in vivo research showed a great potential of using BPs in healing of fractured bones, reducing osteoarthritis, or enhancing ingrowth of bone allografts (5,25,27). It was earlier proposed that the introduction of bisphosphonate compounds can be a very promising procedure connected with the treatment of musculoskeletal disorders in clinical practice (19,27,28). Furthermore, the data obtained in the present study demonstrates that the use of pamidronate as a cocomponent of cement also has some positive effect on muscle homeostasis in rats after the surgery.…”

Section: Resultsmentioning

confidence: 99%

The presence of pamidronate in bone cement affects serum biochemical markers in the rat

Matuszewski¹,

Matuszewska

Jaszek

et al. 2014

Bulletin of the Veterinary Institute in Pulawy

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The main aim of the study was to assess whether the presence of biphosphate pamidronate (PA) in the cement implanted into the tibial bones had any effect on the chosen biochemical markers in rat's serum characterising homeostasis. Forty adult male Wistar rats were divided into two control groups and two experimental groups. Tibial bone of rats in the experimental groups was implanted with PA-enriched cement, whereas the bone in control-group's rats was implanted with cement without PA. Serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) were determined three and six weeks after the surgery. Statistically significant differences in the activities of AST and CK of the rats after implantation with non-enriched cement when compared to rats given PA-enriched cement implantation, were found. Six weeks after treatment, AST levels decreased significantly in rats with PA-enriched cement, whereas rats in the control group (implanted with non-enriched cement) demonstrated a significant increase in AST activity in comparison to the same values determined after three weeks and values of PA-enriched cement rats determined after six weeks. The activities of CK were higher in rats with PA-enriched implants than in the control group three weeks after surgery, but six weeks after the treatment, rats implanted with enriched cement reached lower values than animals implanted with non-enriched cement. The use of PA in the cement had also some positive effect on the homeostasis of the rats after the surgery and a positive influence on the post operative muscle regeneration process.

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Distal tibial fracture repair in a neurofibromatosis type 1-deficient mouse treated with recombinant bone morphogenetic protein and a bisphosphonate

Cited by 38 publications

References 37 publications

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

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

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

The presence of pamidronate in bone cement affects serum biochemical markers in the rat

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