Effectiveness of recombinant human bone morphogenetic protein-7 in the management of congenital pseudoarthrosis of the tibia: a randomised controlled trial

Das, Sakti; Ganesh, G. Shankar; Pradhan, Sudhakar; Singh, Deepak Kumar; Mohanty, Ram Narayan

doi:10.1007/s00264-014-2361-7

Cited by 32 publications

(16 citation statements)

References 36 publications

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“…Since in prior reported cases of NF1, PA was invariably secondary to NF, our patient did not present enough early symptoms to receive NF1 diagnosis at 4 months when she first manifested PA. Up to one-half of children who are first seen by orthopedists for anterolateral bowing of the tibia will not have a diagnosis of neurofibromatosis 13 .…”

Section: Case Reportmentioning

confidence: 99%

Case Report: Aggressive Tibial Pseudarthrosis as Primary Symptom in Infant with Neurofibromatosis

Reid

Zupan

Sevison

et al. 2016

Preprint

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Neurofibromatosis (NF1) is a rare genetic neurologic disorder with over 30 distinct clinical manifestations, the top 3 of which include café-au-lait spotting, benign tumors and abnormal freckling. Pseudarthrosis (PA), also known as a "false joint," is a rare subset of NF1 symptomology, characterized by bone fractures and nonunion caused by severe bowing of long bones. To date, it is invariably reported as secondary to NF1, commonly at 24 months of age. Here we describe a 4-month old infant who presented with PA as primary symptom, and in absence of an NF1 first-degree relative. Initial manifestation was guarding of the leg and increased irritability upon palpation of the knee, subsequent to light playful jostling. Physician examination revealed gross anterolateral bowing of the left leg. Radiography confirmed tibia-fibula bowing and pathologic transverse fracture at tibia diaphysis, characteristic of PA. Café-au-lait spots developed at 6 months subsequent to PA, but with number and size well below the National Institutes of Health criteria for NF1 diagnosis. At 14 months, exome sequencing established definitive NF1 diagnosis. Treatment involved PA takedown surgery. Although healing was seen after 2 months, complications emerged by 6 months. This case suggests that for primary PA without clear etiology, first-contact and consulting physicians should pay careful attention and be vigilant to timing of clinical onset and severity. Early, severe primary PA warrants accelerated NF1 exome sequencing, suggesting expansion of existing federal guidelines may be necessary to improve detection and prognosis of this rare, debilitating but readily managed condition.

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Section: Case Reportmentioning

confidence: 99%

Case Report: Aggressive Tibial Pseudarthrosis as Primary Symptom in Infant with Neurofibromatosis

Reid

Zupan

Sevison

et al. 2016

Preprint

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“…Treatments for such fractures in NF1 patients involve stabilization and fixation of the area and/or grafting of bone and osteoid tissue onto the site [12][13][14]. In addition to these surgical procedures, pharmaceutical-based treatments have been attempted to aid bone tissue regeneration such as the use of bisphosphonates, bone morphogenetic protein 2, and/or bone morphogenetic protein 7 [15][16][17][18]. The efficacy of these treatments is variable and can lead to unresolved pseudarthrosis, in some cases even requiring amputation of the limb [10].…”

Section: Introductionmentioning

confidence: 99%

Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair

Baht

Nadesan

Silkstone

et al. 2017

Bone

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Patients with Neurofibromatosis type 1 display delayed fracture healing and the increased deposition of fibrous tissue at the fracture site. Severe cases can lead to non-union and even congenital pseudarthrosis. Neurofibromatosis type 1 is caused by a mutation in the NF1 gene and mice lacking the Nf1 gene show a fracture repair phenotype similar to that seen in patients. Tissue from the fracture site of patients with Neurofibromatosis type 1 and from mice deficient in the Nf1 gene both show elevated levels of β-catenin protein and activation of β-catenin mediated signaling. Constitutively elevated β-catenin leads to a delayed and fibrous fracture repair process, and (RS)-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine (Nefopam, a centrally-acting, non-narcotic analgesic agent) inhibits β-catenin mediated signaling during skin wound repair. Here we investigate Nefopam's potential as a modulator of bone repair in mice deficient in Nf1. Mice were treated with Nefopam and investigated for bone fracture repair. Bone marrow stromal cells flushed from the long bones of unfractured mice were treated with Nefopam and investigated for osteogenic potential. Treatment with Nefopam was able to lower the β-catenin level and the Axin2 transcript level in the fracture calluses of Nf1 deficient mice. Cultures from the bone marrow of Nf1 mice had significantly lower osteoblastic colonies and mineralized nodules, which was increased when cells were cultured in the presence of Nefopam. Fracture calluses were harvested and analyzed 14days and 21days after injury. Nf1 calluses had less bone, less cartilage, and higher fibrous tissue content than control calluses. Treatment with Nefopam increased the bone and cartilage content and decreased the fibrous tissue content in Nf1 calluses. These findings present a potential treatment for patients with Neurofibromatosis 1 in the context of bone repair. Since Nefopam is already in use in patient care, it could be rapidly translated to the clinical setting.

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“…Together with co-activators, corepressors, and other transcription factors, the Smad complex regulates gene expression Table 1 Simplified demonstration of the most important stages of chondrogenesis -----Dashed line symbolizes the fluent change between the stages ====Double line separates the ossification stage because this process is not directly involved in the formation of joint depends on matrix metalloproteinase (MMP) activity. However, despite the increased use of BMPs to improve bone healing, it was recently reported that administration of human BMP-7 and autologous bone grafting is no better than autologous grafting alone in patients with congenital pseudoarthrosis of the tibia [33].…”

Section: The Role Of Growth Factors In Chondrogenesismentioning

confidence: 99%

The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration

Augustyniak

Trzeciak

Richter

et al. 2014

International Orthopaedics (SICOT)

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Purpose The use of stem cells in regenerative medicine offers hope to treat numerous orthopaedic disorders, including articular cartilage defects. Although much research has been carried out on chondrogenesis, this complicated process is still not well understood and much more research is needed. The present review provides an overview of the stages of chondrogenesis and describes the effects of various growth factors, which act during the multiple steps involved in stem celldirected differentiation towards chondrocytes. Methods The current literature on stem cell-directed chondrogenesis, in particular the role of members of the transforming growth factor-β (TGF-β) superfamily-TGF-βs, bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs)-is reviewed and discussed. Results Numerous studies have reported the chondrogenic potential of both adult-and embryonic-like stem cells and the role of growth factors in programming differentiation of these cells towards chondrocytes. Mesenchymal stem cells (MSCs) are adult multipotent stem cells, whereas induced pluripotent stem cells (iPSC) are reprogrammed pluripotent cells. Although better understanding of the processes involved in the development of cartilage tissues is necessary, both cell types may be of value in the clinical treatment of cartilage injuries or osteoarthritic cartilage lesions. Conclusions MSCs and iPSCs both present unique characteristics. However, at present, it is still unclear which cell type is most suitable in the treatment of cartilage injuries.

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Effectiveness of recombinant human bone morphogenetic protein-7 in the management of congenital pseudoarthrosis of the tibia: a randomised controlled trial

Cited by 32 publications

References 36 publications

Case Report: Aggressive Tibial Pseudarthrosis as Primary Symptom in Infant with Neurofibromatosis

Case Report: Aggressive Tibial Pseudarthrosis as Primary Symptom in Infant with Neurofibromatosis

Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair

The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration

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