Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype

Nobuhiro Kamiya, Ryosuke Yamaguchi, Olumide Aruwajoye, Audrey J. Kim, Gen Kuroyanagi, Matthew Phipps, Naga Suresh Adapala, Jian Q. Feng, Harry K.W. Kim

Research output: Contribution to journalArticle

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Abstract

Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia-like bone phenotype. Serum FGF23 levels were 4 times increased in cKO mice compared with age-matched controls. In addition, calcium-phosphorus metabolism was significantly altered (calcium reduced; phosphorus reduced; parathyroid hormone [PTH] increased; 1,25(OH)2D decreased). Bone histomorphometry showed dramatically increased osteoid parameters, including osteoid volume, surface, and thickness. Dynamic bone histomorphometry revealed reduced bone formation rate and mineral apposition rate in the cKO mice. TRAP staining showed a reduced osteoclast number. Micro-CT demonstrated thinner and porous cortical bones in the cKO mice, in which osteocyte dendrites were disorganized as assessed by electron microscopy. Interestingly, the cKO mice exhibited spontaneous fractures in long bones, as found in NF1 patients. Mechanical testing of femora revealed significantly reduced maximum force and stiffness. Immunohistochemistry showed significantly increased FGF23 protein in the cKO bones. Moreover, primary osteocytes from cKO femora showed about eightfold increase in FGF23 mRNA levels compared with control cells. The upregulation of FGF23 was specifically and significantly inhibited by PI3K inhibitor Ly294002, indicating upregulation of FGF23 through PI3K in Nf1-deficient osteocytes. Taken together, these results indicate that Nf1 deficiency in osteocytes dramatically increases FGF23 production and causes a mineralization defect (ie, hyperosteoidosis) via the alteration of calcium-phosphorus metabolism. This study demonstrates critical roles of neurofibromin in osteocytes for osteoid mineralization.

Original languageEnglish
Pages (from-to)1716-1726
Number of pages11
JournalJournal of Bone and Mineral Research
Volume32
Issue number8
DOIs
Publication statusPublished - Aug 1 2017
Externally publishedYes

Fingerprint

Osteocytes
Osteomalacia
Phenotype
Bone and Bones
Neurofibromin 1
Phosphorus
Calcium
Phosphatidylinositol 3-Kinases
Femur
Up-Regulation
Genetic Databases
Spontaneous Fractures
Neurofibromatosis 1
Metabolome
Bone Remodeling
Osteoclasts
Dendrites
Parathyroid Hormone
Serum
Osteogenesis

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype. / Kamiya, Nobuhiro; Yamaguchi, Ryosuke; Aruwajoye, Olumide; Kim, Audrey J.; Kuroyanagi, Gen; Phipps, Matthew; Adapala, Naga Suresh; Feng, Jian Q.; Kim, Harry K.W.

In: Journal of Bone and Mineral Research, Vol. 32, No. 8, 01.08.2017, p. 1716-1726.

Research output: Contribution to journalArticle

Kamiya, N, Yamaguchi, R, Aruwajoye, O, Kim, AJ, Kuroyanagi, G, Phipps, M, Adapala, NS, Feng, JQ & Kim, HKW 2017, 'Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype', Journal of Bone and Mineral Research, vol. 32, no. 8, pp. 1716-1726. https://doi.org/10.1002/jbmr.3155
Kamiya, Nobuhiro ; Yamaguchi, Ryosuke ; Aruwajoye, Olumide ; Kim, Audrey J. ; Kuroyanagi, Gen ; Phipps, Matthew ; Adapala, Naga Suresh ; Feng, Jian Q. ; Kim, Harry K.W. / Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype. In: Journal of Bone and Mineral Research. 2017 ; Vol. 32, No. 8. pp. 1716-1726.
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abstract = "Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia-like bone phenotype. Serum FGF23 levels were 4 times increased in cKO mice compared with age-matched controls. In addition, calcium-phosphorus metabolism was significantly altered (calcium reduced; phosphorus reduced; parathyroid hormone [PTH] increased; 1,25(OH)2D decreased). Bone histomorphometry showed dramatically increased osteoid parameters, including osteoid volume, surface, and thickness. Dynamic bone histomorphometry revealed reduced bone formation rate and mineral apposition rate in the cKO mice. TRAP staining showed a reduced osteoclast number. Micro-CT demonstrated thinner and porous cortical bones in the cKO mice, in which osteocyte dendrites were disorganized as assessed by electron microscopy. Interestingly, the cKO mice exhibited spontaneous fractures in long bones, as found in NF1 patients. Mechanical testing of femora revealed significantly reduced maximum force and stiffness. Immunohistochemistry showed significantly increased FGF23 protein in the cKO bones. Moreover, primary osteocytes from cKO femora showed about eightfold increase in FGF23 mRNA levels compared with control cells. The upregulation of FGF23 was specifically and significantly inhibited by PI3K inhibitor Ly294002, indicating upregulation of FGF23 through PI3K in Nf1-deficient osteocytes. Taken together, these results indicate that Nf1 deficiency in osteocytes dramatically increases FGF23 production and causes a mineralization defect (ie, hyperosteoidosis) via the alteration of calcium-phosphorus metabolism. This study demonstrates critical roles of neurofibromin in osteocytes for osteoid mineralization.",
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