Aberrant Myeloid Differentiation Contributes to the Development of Osteoporosis in Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disorder affecting approximately 1 in 3000 individuals worldwide. NF1 results from heritable or spontaneous mutations of the NF1 tumor suppressor gene. NF1 encodes the protein neurofibromin, which functions to negatively regulate Ras-activity. Approximately 50 % of NF1 patients develop osteopenia or osteoporosis, resulting in significantly increased rates of long-bone fracture and morbidity. While defective osteoblast bone anabolism has been implicated as a central factor in the pathogenesis of NF1 associated skeletal deficits, recent data suggest that NF1 (Nf1) haploinsufficiency within the hematopoietic compartment, particularly in osteoclasts and myeloid progenitors, plays a pivotal role in engendering NF1 osseous manifestations. In this chapter, we review the latest data from clinical studies and murine models delineating a critical role for hematopoietic compartment, myeloid progenitors of NF1 (Nf1) haploinsufficient and their progeny-osteoclasts, in the pathogenesis of NF1 associated osteopenia/osteoporosis and discuss putative targets for future therapeutics.

Unusual form of the distal bone defect of ulna with neurofibromatosis type 1

“…There is a great deal of controversy surrounding the timing of surgery, the method, and duration of fixation, [12] and the reason why NF-1 can affect skeletal system is unclear. Rhodes and Yang [13] summarized clinical and murine studies and indicated that the NF-1 (Nf-1) gene dose is vital to the pathogenesis of NF-1-associated skeletal progenitor cells. Also, osteoclasts play a critical role in potentiating osteolytic activity, cooperating with Nf-1-deficient mesenchymal cells and osteoblasts to engender multiple NF-1-associated osseous defects, including osteoporosis, in transgenic mouse models closely recapitulating human disease.…”

Immune system changes in the pathogenesis of neurofibromatosis type 1

“…NF1 + / --предшественники остеоклас тов гиперчувствительны к макрофагальному КСФ, который повышает их миграционные и адгезивные свойства. При этом введение PLX3397 в эксперименте подавляло патологическую активность остеокластов с нормализацией плотности костей [10].…”

“…В связи с этим, помимо опухолевого синдрома, для НФ1 характерна мультисистемность поражения орга низма человека. У 99 % больных НФ1 развиваются Схема строения нейрофибромина и функциональных взаимосвязей его доменов (адаптировано из [8] с разрешения авторов с изменениями) Neurofibromin structure and the functional relationships of its domains (adapted from [8] with the permission of the authors with modifications) Теоретические аспекты и фундаментальные исследования -в практику врача-онколога пятна цвета кофе с молоком (café au lait macules, CALM), у 90 % -веснушчатость, у 81 % -поведенческие рас стройства [9], у 65 % -когнитивный дефицит [5], у 50 % -остеопения или остеопороз [10]. Характерны также иммунопатологические процессы, обусловлен ные нарушением дифференцировки гемопоэтических клеток, о чем свидетельствует повышенный риск раз вития лейкозов у больных НФ1, а также частые мута ции NF1 при спорадических лейкозах.…”

Spinal Manifestations of Neurofibromatosis: An Update

“…Skeletal defects are among the most impactful complications on the quality of life of patients. Bone deformities, osteoporosis, osteopenia, reduction of bone mass density, and spinal osteopathy such as scoliosis among such defects [18]. Although the relative prevalence of spinal defects in neurofibromatosis type 1 is not clear, scoliosis can be considered the most common type of spinal deformity in this illness to the point it is present in 10% to 71% of cases.…”

“…The existence of these spots in the inguinal and the axillary region has the most specificity for NF1 if seen in children [26]. Some of the other forms of manifestations that might take place in patients can be related to optic pathway tumors, for glioma is one of the diseases that may result from this syndrome [18], appearing mostly in young children. Lisch nodules of the iris is one of the other symptoms of this syndrome and musculoskeletal and orthopedic defects and pseudarthrosis are some of the others [4,21,24].…”