Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone

Calcified Tissue International
X YuJ M Hock

Abstract

Approximately 50% of neurofibromatosis type 1 (NF1) patients exhibit skeletal pathology, such as premature osteoporosis or pseudoarthroses. Loss of neurofibromin deregulates Ras signal transduction to affect generation of mitogen-activated protein kinase and Akt, both of which have been implicated in parathyroid hormone (PTH) anabolic mechanisms. Our aim was to determine if loss of neurofibromin impaired the anabolic effect of PTH on bone mass. Nf1 heterozygote (Nf1(+/-)) and wild type (Nf1(+/+)) mice were treated with recombinant human PTH(1-34) or vehicle once daily for 3-28 days. PTH enhanced mRNA expression of c-fos, junB, and fra2 in the distal femur metaphyses of both genotypes; expression of these transcripts was consistently lower in PTH-treated Nf1(+/-) mice. Despite lowered c-fos expression in Nf1(+/-) mice, PTH increased bone mass equivalently in both genotypes by 28 days. Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors. Lower c-fos expression was previously thought to abrogate PTH responsiveness. Our results suggest crosstalk might occur betw...Continue Reading

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Citations

Jun 15, 2007·Journal of Neurosurgery·John M K MislowGary F Rogers
Jul 5, 2007·Acta Paediatrica·Kutluhan YilmazNurten Eskiyurt
Sep 6, 2007·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Aaron SchindelerDavid G Little
Jun 9, 2021·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Laura E ZweiflerLaurie K McCauley

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