المؤلفون: Rhodes, Steven D.^1,2, Zhang, Wei^2,3,4, Yang, Dalong^2,3,4, Yang, Hao², Chen, Shi^2,3, Wu, Xiaohua^2,3, Li, Xiaohong^2,3, Yang, Xianlin^2,3, Mohammad, Khalid S.⁵, Guise, Theresa A.⁵, Bergner, Amanda L.⁶, Stevenson, David A.⁷, Yang, Feng-Chun^1,2,3 fyang@iupui.edu

المصدر: PLoS ONE. Mar2015, Vol. 10 Issue 3, p1-19. 19p.

مصطلحات موضوعية: *SPINE abnormalities, *NEUROFIBROMATOSIS, *HISTOMORPHOMETRY, *SCOLIOSIS, *INTERVERTEBRAL disk diseases, *ACQUISITION of data

مستخلص: Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/−;PeriCre and Nf1flox/−;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/−;PeriCre and Nf1flox/−;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36–60% of Nf1flox/−;PeriCre and Nf1flox/−;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population. [ABSTRACT FROM AUTHOR]

المؤلفون: Yongzheng He¹ (AUTHOR), Rhodes, Steven D.² (AUTHOR), Shi Chen¹ (AUTHOR), Xiaohua Wu¹ (AUTHOR), Jin Yuan¹ (AUTHOR), Xianlin Yang¹ (AUTHOR), Li Jiang¹ (AUTHOR), Xianqi Li³ (AUTHOR), Takahashi, Naoyuki³ (AUTHOR), Mingjiang Xu¹ (AUTHOR), Mohammad, Khalid S.⁴ (AUTHOR), Guise, Theresa A.⁴ (AUTHOR), Feng-Chun Yang¹ (AUTHOR) fyang@iupui.edu

المصدر: PLoS ONE. Nov2012, Vol. 7 Issue 11, Special section p1-9. 9p.

مصطلحات موضوعية: *BONE diseases, *SKELETAL abnormalities, *OSTEOPOROSIS, *OSTEOPENIA, *NEUROFIBROMATOSIS, *MUSCULOSKELETAL system diseases

مستخلص: Skeletal abnormalities including osteoporosis and osteopenia occur frequently in both pediatric and adult neurofibromatosis type 1 (NF1) patients. NF1 (Nf1) haploinsufficient osteoclasts and osteoclast progenitors derived from both NF1 patients and Nf1+/- mice exhibit increased differentiation, migration, and bone resorptive capacity in vitro, mediated by hyperactivation of p21Ras in response to limiting concentrations of macrophage-colony stimulating factor (M-CSF). Here, we show that M-CSF binding to its receptor, c-Fms, results in increased c-Fms activation in Nf1+/- osteoclast progenitors, mediating multiple gain-in-functions through the downstream effectors Erk+/- and p90RSK. PLX3397, a potent and selective c-Fms inhibitor, attenuated M-CSF mediated Nf1+/- osteoclast migration by 50%, adhesion by 70%, and pit formation by 60%. In vivo, we administered PLX3397 to Nf1+/- osteoporotic mice induced by ovariectomy (OVX) and evaluated changes in bone mass and skeletal architecture. We found that PLX3397 prevented bone loss in Nf1+/--OVX mice by reducing osteoclast differentiation and bone resorptive activity in vivo. Collectively, these results implicate the M-CSF/c-Fms signaling axis as a critical pathway underlying the aberrant functioning of Nf1 haploinsufficient osteoclasts and may provide a potential therapeutic target for treating NF1 associated osteoporosis and osteopenia. [ABSTRACT FROM AUTHOR]

المؤلفون: Wu, Xiaohua, Chen, Shi, He, Yongzheng, Rhodes, Steven D., Mohammad, Khalid S., Li, Xiaohong, Xianlin Yang, Li Jiang, Nalepa, Grzegorz, Snider, Paige, Robling, Alexander G., Clapp, D. Wade, Conway, Simon J., Guise, Theresa A., Feng-Chun Yang

المصدر: PLoS ONE; 2011, Vol. 6 Issue 9, p1-13, 13p

مصطلحات موضوعية: HAPLOIDY, HEMATOPOIETIC system, SPONTANEOUS fractures, LABORATORY rats, NEUROFIBROMATOSIS, BONE marrow cells, BIOLOGY experiments, SKELETAL dysplasia

مستخلص: Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/ progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre⁺;Nf1^flox/- and Col2.3Cre⁺;Nf1^flox/-mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations. [ABSTRACT FROM AUTHOR]

: Copyright of PLoS ONE is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Yongzheng He, Staser, Karl, Rhodes, Steven D., Yaling Liu, Xiaohua Wu, Su-Jung Park, Jin Yuan, Xianlin Yang, Xiaohong Li, Li Jiang, Shi Chen, Feng-Chun Yang

المصدر: PLoS ONE; 2011, Vol. 6 Issue 9, p1-10, 10p

مصطلحات موضوعية: EXTRACELLULAR signal-regulated kinases, GENE expression, BONE resorption, PROTEIN synthesis, CELL proliferation, CELL differentiation, OSTEOCLASTS, PHENOTYPES, NOONAN syndrome

مستخلص: The extracellular signal-regulated kinases (ERK1 and 2) are widely-expressed and they modulate proliferation, survival, differentiation, and protein synthesis in multiple cell lineages. Altered ERK1/2 signaling is found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, Neurofibromatosis type 1, and Cardio-facio-cutaneous syndrome, suggesting that MEK-ERK signals regulate human skeletal development. Here, we examine the consequence of Erk1 and Erk2 disruption in multiple functions of osteoclasts, specialized macrophage/monocyte lineage-derived cells that resorb bone. We demonstrate that Erk1 positively regulates osteoclast development and bone resorptive activity, as genetic disruption of Erk1 reduced osteoclast progenitor cell numbers, compromised pit formation, and diminished M-CSFmediated adhesion and migration. Moreover, WT mice reconstituted long-term with Erk1^-/- bone marrow mononuclear cells (BMMNCs) demonstrated increased bone mineral density as compared to recipients transplanted with WT and Erk2^-/- BMMNCs, implicating marrow autonomous, Erk1-dependent osteoclast function. These data demonstrate Erk1 plays an important role in osteoclast functions while providing rationale for the development of Erk1-specific inhibitors for experimental investigation and/or therapeutic modulation of aberrant osteoclast function. [ABSTRACT FROM AUTHOR]

: Copyright of PLoS ONE is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)