Ras Dependent Paracrine Secretion of Osteopontin by Nf1+/− Osteoblasts Promote Osteoclast Activation in a Neurofibromatosis Type I Murine Model

Li, Huijie; Liu, Yaling; Zhang, Qi; Jing, Yongmin; Chen, Shi; Song, Zhao-Hui; Yan, Jincheng; Li, Yan; Wu, Xiaohua; Zhang, Xianghong; Zhang, Yingze; Case, Jamie; Yu, Menggang; Ingram, David A.; Yang, Feng Chun

doi:10.1203/pdr.0b013e3181a1c607

Cited by 25 publications

(19 citation statements)

References 31 publications

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“…Osteoclastogenesis can be activated by RAS signaling, such as occurs in Nf1 deficiency (5,11,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). We observed a gain in the number of osteoclasts at the Nf1-null murine fracture site, in agreement with previous studies (51)(52)(53)(54)(55)(56)(57).…”

Section: Discussionsupporting

confidence: 91%

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

et al. 2016

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Tibial pseudarthrosis causes substantial morbidity in patients with neurofibromatosis type 1 (NF1). We studied tibial pseudarthrosis tissue from patients with NF1 and found elevated levels of b-catenin compared to unaffected bone. To elucidate the role of b-catenin in fracture healing, we used a surgically induced tibial fracture model in conditional knockout (KO) Nfl (Nf1 flox/flox ) mice. When treated with a Cre-expressing adenovirus (Ad-Cre), there was a localized knockdown of Nf1 in the healing fracture and a subsequent development of a fibrous pseudarthrosis. Consistent with human data, elevated b-catenin levels were found in the murine fracture sites. The increased fibrous tissue at the fracture site was rescued by local treatment with a Wingless-type MMTV integration site (Wnt) antagonist, Dickkopf-1 (Dkk1). The murine pseudarthrosis phenotype was also rescued by conditional b-catenin gene inactivation. The number of colony-forming unit osteoblasts (CFU-Os), a surrogate marker of undifferentiated mesenchymal cells able to differentiate to osteoblasts, correlated with the capacity to form bone at the fracture site. Our findings indicate that the protein level of b-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of b-catenin in NF1 causes a shift away from osteoblastic differentiation resulting in a pseudarthrosis in vivo. These results support the notion that pharmacological modulation of b-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. b-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications. FASEB J. 30, 3227-3237 (2016). www.fasebj.orgNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by activated RAS signaling and mutations that dysregulate the NF1 protein (neurofibromin). NF1-related skeletal abnormalities are an important cause of morbidity with osteoporosis, scoliosis, and tibial dysplasia affecting more than half of affected individuals. Tibial dysplasia typically starts with anterolateral tibial bowing, characteristically progressing to a fracture that will not heal, termed a pseudarthrosis. Normal fracture healing is characterized by the deposition of new bone from osteoblasts, followed by a period of remodeling in which osteoclasts are active. At the tibial pseudarthrosis fracture site, however, is fibrous hamartoma tissue contain cells that do not undergo osteoblastic differentiation form. There is also an increase in osteoclastogenic activity at the fracture site, when compared to the healing in a normal fractured tibia (1-4). Because tibial pseudarthrosis is refractive to medical treatment, the only management options are surgical. For those continuing to experience chronic pain and impaired mobility, an amputation may be required if other treatments are not effective.Germline heterozygous mutations of NF1 cause NF1. In some but not all NF1-related tibial pseudarthrosis, a second hit to the NF1 gen...

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Section: Discussionsupporting

confidence: 91%

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

et al. 2016

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“…However, increased expression of osteopontin and osteocalcin is an indicator of transformation of VSMC to osteoblast-like cells as well as an indicator of vascular calcification [27,28]. Since the amount of osteopontin is decreased in the presence of Mg 2+ , Mg 2+ inhibiting the formation of hydroxyapatite crystals [29,30]. In addition, the amount of osteocalcin in aortic segments incubated in the presence of Mg 2+ was significantly lower than in its absence.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Magnesium and Clinical Biomarkers on Inhibition of Vascular Calcification

et al. 2011

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Background: Arteriosclerosis and cardiovascular disease are strongly associated with vascular calcification. Hyperphosphatemia is an essential risk factor for increased vascular calcification. End-stage renal disease (ESRD) patients could serve as an in vivo model for accelerated calcification. This study focuses on the most likely protective effects of magnesium ion (Mg²⁺) on phosphate-induced vascular calcification ex vivo/in vitro. Furthermore, plasma Mg²⁺ concentrations of ESRD and healthy controls were investigated for association with surrogate parameters of vascular calcification in vivo. Methods: Aortic segments of male Wistar-Kyoto rats were incubated and the phosphate concentration of the medium was elevated. The aortic segments were incubated in the absence and presence of MgCl₂; tissue calcification was quantified by different methods. Serum Mg²⁺ concentrations of patients with chronic kidney disease (CKD stage 5; ESRD) and patients without CKD (controls) were associated with carotid intima media thickness (IMT) and aortic pulse wave velocity (PWV) as surrogate parameter for arteriosclerosis and arterial stiffening. Results: Incubation of aortic segments in the presence of β-glycerophosphate and NaH₂PO₄ caused an increased tissue Ca²⁺ deposition compared to control conditions. This increased amount of Ca²⁺ in the aortic rings was significantly decreased in the presence of Mg²⁺. In CKD patients, but not in controls, magnesium serum concentration was associated with the IMT of the carotid arteries. In addition, CKD patients with higher magnesium serum concentration had a significantly lower PWV. Discussion and Conclusion: Elevated phosphate concentrations in the culture media induce ex vivo/in vitro medial calcification in intact rat aortic rings in the presence of alkaline phosphatase. Mg²⁺ ions reduced ex vivo/in vitro vascular calcification despite increased phosphate concentration. This hypothesis is additionally based on the fact that CKD patients with high Mg² serum levels had significantly lower IMT and PWV values, which may result in a lower risk for cardiovascular events and mortality in these patients. Therefore, Mg²⁺ supplementation may be an option for treatment and prevention of vascular calcification resulting in a reduction of cardiovascular events in CKD patients.

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“…Each group of cultured cells was harvested after 0, 1, 6, and 24 hours of COM treatment and used for flow cytometry and RT-PCR. For the neutralization of crystal binding molecules, 2 mg/ml OPN antibody (R&D Systems), 63 2 mg/ml MCP-1 antibody (R&D Systems), 64 and 10 mg/ml CD44 antibody (Calbiochem) 65 were added to dishes of M1Mws and M2Mws 6 hours before COM treatment.…”

Section: Induction Of M1mws and M2mws From Bone Marrow Cell Culturesmentioning

confidence: 99%

Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation

Taguchi

Okada

Kitamura

et al. 2014

Journal of the American Society of Nephrology

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We recently reported evidence suggesting that migrating macrophages (Mws) eliminate renal crystals in hyperoxaluric mice. Mws can be inflammatory (M1) or anti-inflammatory (M2), and colony-stimulating factor-1 (CSF-1) mediates polarization to the M2Mw phenotype. M2Mws promote renal tissue repair and regeneration, but it is not clear whether these cells are involved in suppressing renal crystal formation. We investigated the role of M2Mws in renal crystal formation during hyperoxaluria using CSF-1-deficient mice, which lack M2Mws. Compared with wild-type mice, CSF-1-deficient mice had significantly higher amounts of renal calcium oxalate crystal deposition. Treatment with recombinant human CSF-1 increased the expression of M2-related genes and markedly decreased the number of renal crystals in both CSF-1-deficient and wild-type mice. Flow cytometry of sorted renal Mws showed that CSF-1 deficiency resulted in a smaller population of CD11b + F4/80 + CD163 + CD206 hi cells, which represent M2-like Mws. Additionally, transfusion of M2Mws into CSF-1-deficient mice suppressed renal crystal deposition. In vitro phagocytosis assays with calcium oxalate monohydrate crystals showed a higher rate of crystal phagocytosis by M2-polarized Mws than M1-polarized Mws or renal tubular cells. Gene array profiling showed that CSF-1 deficiency resulted in disordered M2-and stone-related gene expressions. Collectively, our results provide compelling evidence for a suppressive role of CSF-1 signaling in renal crystal formation.

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Ras Dependent Paracrine Secretion of Osteopontin by Nf1+/− Osteoblasts Promote Osteoclast Activation in a Neurofibromatosis Type I Murine Model

Cited by 25 publications

References 31 publications

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

β‐Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications

Relationship between Magnesium and Clinical Biomarkers on Inhibition of Vascular Calcification

Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation

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