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1.  Sinonasal Schwannoma with New Bone Formation Expressing Bone Morphogenic Protein 
Schwannoma is a benign tumor that arises from the sheath of myelinated nerve fibers and may occur in any part of the body. Osteogenesis in schwannoma is extremely rare and, to date, new bone formation in sinonasal schwannoma has not yet been reported. Here, we describe the first reported case of sinonasal schwannoma with new bone formation. The tumor was successfully treated by endoscopic sinus surgery, and the patient showed no evidence of recurrence 24 months postoperatively. Immunohistochemically, the tumor expressed bone morphogenic protein 4, indicating a possible role of this protein in the new bone formation in schwannomas.
PMCID: PMC3010644  PMID: 21197441
2.  Are Endogenous BMPs Necessary for Bone Healing during Distraction Osteogenesis? 
Previous reports suggest the application of exogenous BMPs can accelerate bone formation during distraction osteogenesis (DO). However, there are drawbacks associated with the use of exogenous BMPs. A possible alternative to the use of exogenous BMPs is to upregulate the expression of endogenous BMPs. Since DO results in spontaneously generated de novo bone formation in a uniform radiographic, histological, and biomechanical temporal sequence, a genetically engineered model lacking endogenous BMP2 should have measurable deficits in bone formation at different time points. We performed DO on BMP2 fl/+ and BMP2 fl/+ cre mice using a miniature Ilizarov fixator. Distracted samples were collected at various time points and analyzed using Real Time-quantitative PCR, μCT, radiology, immunohistochemistry, histology, and biomechanical testing. Immunohistochemical studies of 34-day heterozygous samples showed reduced expression of BMP2, BMP7, BMPR1a, ACTR1, and ACTR2b. μCT analysis of 51-day heterozygous samples revealed a decrease in trabecular number and increase in trabecular separation. Biomechanical testing of 51-day heterozygous samples revealed decreased stiffness and increased ultimate displacement. Radiological analysis showed the heterozygotes contained a decreased bone fill score at 17, 34, and 51 days. These data suggest endogenous BMPs are important for bone healing and manipulating endogenous BMPs may help accelerate bone consolidation during DO.
PMCID: PMC2772912  PMID: 19760469
3.  Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities 
Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn). In contrast, treatment with rhBMP12 or rhBMP13 resulted in a dose-dependent induction of a tendon-specific gene (Thbs4) expression with no detectable activation of SMAD 1, 5, and 8. Differential regulation of Thbs4 and Ocn has potential utility as an in vitro biomarker for induction of tenogenic signaling. Such an assay also permits the ability to distinguish between the activities of different BMPs and may prove useful in studies on the molecular mechanisms of BMP tenogenic activity.
PMCID: PMC3154542  PMID: 21702718
Bone morphogenetic proteins; thrombospondin 4; tendon markers
4.  Fascin Over Expression is Associated with Dysplastic Changes in Sinonasal Inverted Papillomas: A Study of 47 Cases 
Head and Neck Pathology  2009;3(3):212-216.
Sinonasal inverted papilloma (IP) is a primary benign lesion with a tendency for local recurrence. Malignant transformation may develop in up to 15% of cases. Fascin (Fascin 1) is an actin cross-link binding protein required for the formation of actin-based cell-surface protrusions and cell motility. Fascin up-regulation in lung, gastric, breast and hepatobiliary carcinomas correlates with aggressiveness and decreased survival. Here we evaluate immunohistochemical expression of fascin in 47 sinonasal IPs from 34 patients. Fascin over-expression is significantly more common in sinonasal IP with high-grade dysplasia than in those with no dysplastic or low-grade dysplastic epithelium (P = 0.0001). No significant change in fascin expression is seen with recurrence. Over expression of fascin in high-grade dysplastic epithelium in IP may be associated with tumor progression and malignant transformation.
PMCID: PMC2811625  PMID: 20596974
Fascin; Sinonasal inverted papilloma; Dysplasia; Malignant transformation; Immunohistochemistry
5.  BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways 
International Orthopaedics  2007;31(6):759-765.
We have recently shown that human recombinant BMP-6 (rhBMP-6), given systematically, can restore bone in animal models of osteoporosis. To further elucidate the underlying mechanisms of new bone formation following systemic application of BMPs, we conducted gene expression profiling experiments using bone samples of oophrectomised mice treated with BMP-6. Gene set enrichment analysis revealed enrichment of insulin-like growth factor-I and epidermal growth factor related pathways in animals treated with BMP-6. Significant upregulation of IGF-I and EGF expression in bones of BMP-6 treated mice was confirmed by quantitative PCR. To develop an in vitro model for evaluation of the effects of BMP-6 on cells of human origin, we cultured primary human osteoblasts. Treatment with rhBMP-6 accelerated cell differentiation as indicated by the formation of mineralised nodules by day 18 of culture versus 28–30 days in vehicle treated cultures. In addition, alkaline phosphatase gene expression and activity were dramatically increased upon BMP-6 treatment. Expression of IGF-I and EGF was upregulated in human osteoblast cells treated with BMP-6. These results collectively indicate that BMP-6 exerts its osteoinductive effect, at least in part, through IGF-I and EGF pathways, which can be observed both in a murine model of osteopenia and in human osteoblasts.
PMCID: PMC2266664  PMID: 17634942
6.  Bone morphogenetic proteins: The anomalous molecules 
Bone is unique of all the tissues in the vertebrate organism. When injured, it heals by formation of new bone. Bone morphogenetic proteins (BMPs) are powerful inductors of the osteogenic activity during the embryologic bone formation phase and in cases of bone healing. They have proliferative effects on different cellular types, showing chemotactic properties and are able to induce mesenchymal cells differentiation into osteoblastic and chondroblastic line cells. Both primary cells and cell lines have been shown to respond to BMPs. Further the ability of embryonic cells to respond to BMPs by differentiating into cartilage and bone cells suggests that they are involved in the development of embryonic skeletal system. In addition, these proteins can also promote the angiogenesis, regulate the activity of some growth factors, and affect the production of these growth factors, which is helpful for the osteogenesis. BMPs have been considered as the most potent growth factors that can promote the bone regeneration. Thus, the aim of this review is to emphasize on the unique nature of the BMP molecules regarding their structure, classification, signaling mechanism, etc., as BMPs are the only molecules which show such deviation from the normal order, type. This will further help in understanding the role of BMPs and their potential advances which are necessary to facilitate the process of regeneration in periodontics.
PMCID: PMC3808010  PMID: 24174749
Bone; growth factors; healing; repair
7.  Improvement of osteogenic potential of biphasic calcium phosphate bone substitute coated with two concentrations of expressed recombinant human bone morphogenetic protein 2 
The aim of this study was to determine whether biphasic calcium phosphate (BCP) bone substitute with two different concentrations of Escherichia coli-expressed recombinant human bone morphogenetic protein 2 (ErhBMP-2) enhances new bone formation in a standardized rabbit sinus model and to evaluate the concentration-dependent effect of ErhBMP-2.
Standardized, 6-mm diameter defects were made bilaterally on the maxillary sinus of 20 male New Zealand white rabbits. Following removal of the circular bony windows and reflection of the sinus membrane, BCP bone substitute without coating (control group) was applied into one defect and BCP bone substitute coated with ErhBMP-2 (experimental group) was applied into the other defect for each rabbit. The experimental group was divided into 2 subgroups according to the concentration of ErhBMP-2 (0.05 and 0.5 mg/mL). The animals were allowed to heal for either 4 or 8 weeks and sections of the augmented sinus and surrounding bone were analyzed by microcomputed tomography and histologically.
Histologic analysis revealed signs of new bone formation in both the control and experimental groups with a statistically significant increase in bone formation in experimental group 1 (0.05 mg/mL ErhBMP-2 coating) after a 4-week healing period. However, no statistically significant difference was found between experimental group 1 and experimental group 2 (0.5 mg/mL ErhBMP-2 coating) in osteoinductive potential (P<0.05).
ErhBMP-2 administered using a BCP matrix significantly enhanced osteoinductive potential in a standardized rabbit sinus model. A concentration-dependent response was not found in the present study.
PMCID: PMC3439523  PMID: 22977741
Bone morphogenetic protein 2; Bone regeneration; Bone substitute; Maxillary sinus; Rabbits
8.  The use of injectable sonication-induced silk hydrogel for VEGF165 and BMP-2 delivery for elevation of the maxillary sinus floor 
Biomaterials  2011;32(35):9415-9424.
Sonication-induced silk hydrogels were previously prepared as an injectable bone replacement biomaterial, with a need to improve osteogenic features. Vascular endothelial growth factor (VEGF165) and bone morphogenic protein-2 (BMP-2) are key regulators of angiogenesis and osteogenesis, respectively, during bone regeneration. Therefore, the present study aimed at evaluating in situ forming silk hydrogels as a vehicle to encapsulate dual factors for rabbit maxillary sinus floor augmentation. Sonication-induced silk hydrogels were prepared in vitro and the slow release of VEGF165 and BMP-2 from these silk gels was evaluated by ELISA. For in vivo studies for each time point (4 and 12 weeks), 24 sinus floors elevation surgeries were made bilaterally in 12 rabbits for the following four treatment groups: silk gel (group Silk gel), silk gel/VEGF165 (group VEGF), silk gel/BMP-2 (group BMP-2), silk gel/VEGF165/BMP-2 (group V+B) (n=6 per group). Sequential florescent labeling and radiographic observations were used to record new bone formation and mineralization, along with histological and histomorphometric analysis. At week 4, VEGF165 promoted more tissue infiltration into the gel and accelerated the degradation of the gel material. At this time point, the bone area in group V+B was significantly larger than those in the other three groups. At week 12, elevated sinus floor heights of groups BMP-2 and V+B were larger than those of the Silk gel and VEGF groups, and the V+B group had the largest new bone area among all groups. In addition, a larger blood vessel area formed in the remaining gel areas in groups VEGF and V+B. In conclusion, VEGF165 and BMP-2 released from injectable and biodegradable silk gels promoted angiogenesis and new bone formation, with the two factors demonstrating an additive effect on bone regeneration. These results indicate that silk hydrogels can be used as an injectable vehicle to deliver multiple growth factors in a minimally invasive approach to regenerate irregular bony cavities.
PMCID: PMC3384686  PMID: 21889205
9.  Magnetic Resonance Imaging Versus Computed Tomography and Different Imaging Modalities in Evaluation of Sinonasal Neoplasms Diagnosed by Histopathology 
The study purpose was to detect the value of magnetic resonance imaging (MRI) compared to computed tomography (CT) and different imaging modalities as conventional radiology in evaluation of sinonasal neoplasms diagnosed by Histopathology.
Thirty patients (16 males and 14 females) were complaining of symptoms related to sinonasal tract. After thorough clinical and local examination, the patients were subjected to the following: conventional radiography, CT, MRI, and histopathological examination.
The nasal cavity was the most commonly involved site with sinonasal malignancies followed by the maxillary sinuses. The least commonly affected site was the frontal sinuses. Benign sinonasal tumors were present in 14 cases. The most common benign lesion was juvenile nasopharyngeal angiofibroma (6 cases), followed by inverted papilloma (3 cases). While malignant sinonasal tumors were present in 16 cases, squamous cell carcinoma was present in 5 cases, and undifferentiated carcinoma, in 3 cases. Lymphoepithelioma and non-Hodgkin lymphomas were present in 2 cases each, while adenocarcinoma, chondrosarcoma, adenoid cystic carcinoma, and rhabdomyosarcoma were present in 1 case each.
MRI with its superior soft tissue contrast and multiplanar capability is superior to CT in pretreatment evaluation of primary malignant tumors of sinonasal cavity.
PMCID: PMC3791956  PMID: 24179408
magnetic resonance imaging; computed tomography; sinonasal tumor
10.  Evaluation of Correlation of Cell Cycle Proteins and Ki-67 Interaction in Paranasal Sinus Inverted Papilloma Prognosis and Squamous Cell Carcinoma Transformation 
BioMed Research International  2014;2014:634945.
The recurrent sinonasal inverted papilloma (IP) could be transformed to sinonasal squamous cell carcinoma. We use protein expression patterns by immunohistochemical method to see whether the expression of p53, p16, p21, and p27 belongs to cell-cycle-regulators and PCNA (proliferating cell nuclear antigen) and Ki-67 the proliferation markers in sixty patients with sinonasal inverted papilloma, and 10 of them with squamous cell carcinoma transformation. Significantly elevated levels of Ki-67, p27, and PCNA in IP with squamous cell carcinoma transformation of sinonasal tract compared with inverted papilloma were revealed. No variation of p16, p21, PLUNC (palate, lung, and nasal epithelium clone protein) and p53 expression was correlated to sinonasal IP malignant transformation by multivariate survey. However, we found elevated PLUNC expression in IPs with multiple recurrences. Finally, we found that PCNA, p27 may interact with CDK1 which promote IP cell proliferation and correlate to sinonasal squamous cell carcinoma. Ki-67 could work throughout the cell cycles to cause malignant transformation. In conclusion, this is a first study showing the correlation of Ki-67, PCNA interacted with CDK1 might lead to malignant transformation. Elevated PLUNC expression in the sinonasal IPs was related to multiple recurrences in human.
PMCID: PMC4075189
11.  BMP4 Promotes Prostate Tumor Growth in Bone Through Osteogenesis 
Cancer research  2011;71(15):5194-5203.
Induction of new bone formation is frequently seen in the bone lesions from prostate cancer (PCa). However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, two xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from PCa bone metastases. When implanted subcutaneously in SCID mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (“secretome”) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of BMP-4 and several cytokines including IL-8, Gro, and CCL2. We demonstrated that BMP-4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treating with BMP-4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP-4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of PCa in bone.
PMCID: PMC3148283  PMID: 21670081
PCa; bone metastasis; chemokines; cytokines; osteoblast
12.  Radiotherapy for inverted papilloma: a case report and review of the literature 
Radiology and Oncology  2013;47(1):71-76.
Sinonasal inverted papilloma (IP) is a rare, usually benign tumor arising from the respiratory mucosa of the sinonasal tract. Surgical resection is the treatment of choice. In histologically overt benign IPs (i.e. without associated malignancy) irradiation was employed only anecdotally. The patient with gross residual of benign IP after up-front surgery that was subsequently treated with irradiation is presented and the literature reports on the use of radiotherapy (RT) in this tumor type are reviewed.
Case report
After the surgical treatment the residuum in the region of the sphenoid and adjacent cavernous sinus was irradiated to 54 Gy in 1.8 Gy daily fractions. No recurrence or deterioration of olfaction, hearing or vision was observed 2.6 years post-RT.
Review of the literature
In the literature, six reports were identified with 16 patients describing necessary details on RT and outcome. Twelve of 14 cases (our case included) with gross or subtotal tumor resection and postoperative RT were locally controlled. The lowest and the median irradiation doses were 47.15 Gy and 56.5 Gy, respectively, and the follow-up period ranged between 0.5–20.5 years (median 7.8 years).
RT is safe and valuable treatment option in histologically overt benign IPs. It is indicated when the risk of tumor recurrence after surgery is increased and in inoperable tumors.
PMCID: PMC3573837  PMID: 23450506
inverted papilloma; local control; radiotherapy; surgery
13.  Evaluation of P53, P63, P21, P27, Ki-67 in Paranasal Sinus Squamous Cell Carcinoma and Inverted Papilloma 
Using a molecular genetic approach, we try to confirm the molecular alterations of inverted papilloma and clarify its status as a putative precursor lesion of sinonasal squamous cell carcinoma. To better understand its genetics, we investigated the immunohistochemical protein expression patterns of cell-cycle-regulators p53, p63, p21, p27 and proliferation marker Ki-67 in 22 inverted papilloma and 9 squamous cell carcinoma of the sinonasal tract. Significantly elevated levels of p53 and p63 in squamous cell carcinoma of sinonasal tract compared with inverted papilloma were revealed. Ki-67-stained neoplastic cell nuclei were found in a significantly higher percentage of squamous cell carcinoma of sinonasal tract than in inverted papilloma, whereas no variation of p21 and p27 expression was identified. This work first examined the immunohistochemical overexpression of p63 in sinonasal inverted papilloma and squamous cell carcinoma. In conclusion, this is a first study shedding light on the expression of p63 in tumors of paranasal sinuses.
PMCID: PMC3102174  PMID: 22468256
Inverted papilloma; p63; p53; Sinonasal squamous cell carcinoma; p21; Cell cycle regulators; MIB-1
14.  CXCL12/CXCR4 Signal Axis Plays an Important Role in Mediating Bone Morphogenetic Protein 9-induced Osteogenic Differentiation of Mesenchymal Stem Cells 
Mesenchymal progenitor stem cells (MPCs) are a group of bone marrow stromal progenitor cells processing osteogenic, chondrogenic, adipogenic and myogenic lineages differentiations. Previous studies have demonstrated that bone morphogeneic protein 9(BMP9) is one of the most osteogenic BMPs both in vitro and in vivo, however, the underlying molecular mechanism of osteogenesis induced by BMP9 is needed to be deep explored. Here, we used the recombinant adenoviruses assay to introduce BMP9 into C3H10T1/2 mesenchymal stem cells to elucidate the role of CXCL12/CXCR4 signal axis during BMP9-incuced osteogenic differentiation. The results showed that CXCL12 and CXCR4 expressions were down-regulated at the stage of BMP9-induced osteogenic differentiation, in a dose- and time-dependent. Pretreatment of C3H10T1/2 cells with CXCL12/CXCR4 could significantly affect the early and mid osteogenic markers alkaline phosphatase (ALP), osteocalcin (OCN), the transcription factors of Runx2, Osx, Plzf and Dlx5 expression, through activating the Smad, MAPK signaling pathway. Addition of exogenous CXCL12 did not affect the changes of the late osteogenic marker calcium deposition. Thus, our findings suggest a co-requirement of the CXCL12/CXCR4 signal axis in BMP9-induced the early- and mid-process of osteogenic differentiation of MSCs.
PMCID: PMC3739017  PMID: 23935395
CXCL 12; CXCR4; Bone Morphogenetic Protein 9; Mesenchymal Stem Cells; Osteogenic Differentiation.
15.  First Evidence of Bone Morphogenetic Protein 1 Expression and Activity in Sheep Ovarian Follicles1 
Biology of Reproduction  2010;83(1):138-146.
Bone morphogenetic protein (BMP) 1 is a vertebrate metalloproteinase of the astacin family. BMP1 plays a key role in regulating the formation of the extracellular matrix (ECM), particularly by processing the C-propeptide of fibrillar procollagens. BMP1 also promotes BMP signaling by releasing BMP signaling molecules from complexes with the BMP-antagonist chordin. As a result of BMP1′s dual role in both ECM formation and BMP signaling, we hypothesized that BMP1 could play a role in ovarian physiology. Using the sheep ovary as a model system, we showed that BMP1 was expressed in the ovary throughout early fetal stages to adulthood. Furthermore, in adult ovaries, BMP1 was expressed along with chordin, BMP4, and twisted gastrulation, which together form an extracellular regulatory complex for BMP signaling. Within ovine ovaries, immunohistochemical localization demonstrated that BMP1 was present in granulosa cells at all stages of follicular development, from primordial to large antral follicles, and that the levels of BMP1 were not affected by the final follicle selection mechanism. In cultured granulosa cells, BMP1 expression was not affected by gonadotropins, but BMP4 and activin A had opposing effects on the levels of BMP1 mRNA. BMP1 appeared to be secreted into the follicular fluid of antral follicles, where it is able to exert procollagen C-proteinase and chordinase activities. Interestingly, BMP1 activity in follicular fluid decreased with follicular growth.
Enzymatically active bone morphogenetic protein 1 (BMP1) is produced by granulosa cells and is present in the follicular fluid of ovine ovarian follicles.
PMCID: PMC2888967  PMID: 20357269
BMP1; follicle; follicular development; granulosa cells; ovary
16.  Regeneration of Bone- and Tendon/Ligament-Like Tissues Induced by Gene Transfer of Bone Morphogenetic Protein-12 in a Rat Bone Defect 
Journal of Tissue Engineering  2010;2010:891049.
Members of the bone morphogenetic protein (BMP) family have diverse physiological roles. For instance, BMP-2 stimulates osteogenesis, while BMP-12 induces the formation of tendon/ligament-like tissues. Here, we designed a study to determine whether BMP-12 has bone and/or cartilage regeneration abilities similar to those of BMP-2. We implanted plasmid vectors encoding either BMP-2 or BMP-12 in rats with femur defects, and monitored the bone healing process for 8-weeks. The BMP-12 transgene induced prominent fibrogenesis by 2 weeks, with bone substitution occurring by 8 weeks. BMP-2, however, was associated predominantly with osteogenesis throughout the 8 week period. Thus, we conclude that BMP-12 does not function similarly to BMP-2 during bone healing. Further work is needed to better understand the mechanisms by which it stimulates bony growths to replace the connective tissues formed during the first stages of bone healing.
PMCID: PMC3040506  PMID: 21350647
17.  Tissue remodeling gene expression in a murine model of chronic rhinosinusitis 
The Laryngoscope  2012;122(4):711-717.
The Matrix Metalloproteinase (MMP), Fibroblast Growth Factor (FGF) and Bone Morphogenetic Protein (BMP) families regulate tissue remodeling in many normal and pathophysiologic processes. We hypothesize that induction of chronic sinonasal inflammation will be associated with changes in regulation of these tissue remodeling cytokines.
Balb/c mice aged 8–12 weeks were sensitized and treated with intranasal Aspergillus fumigatis (AF) three times per week for 1 week, 3 weeks, 2 months and 3 months (n=8 each time point). Sinonasal tissues were evaluated for changes in MMP, FGF and BMP regulation using standard RT-PCR techniques. Additional snouts were processed for histology and immunohistochemistry. Untreated mouse snouts of identical age were used as controls.
Significant upregulation of MMP8 was observed at 2 months, and MMP1a, MMP7, MMP8 and MMP12 were all significantly upregulated at 3 months. FGF3 was significantly upregulated at 3 weeks and 3 months, and FGF5, FGF6 and FGF8 were all significantly upregulated at 3 months. BMP8b and BMP9 were significantly upregulated at 3 months. Histologic analysis revealed mucosal, stromal and mucin gland hypertrophy, increased mucin production, and metaplasia with loss of cilia. Antibody staining was strongly positive in the AF treated group.
Induction of CRS is associated with time-dependent changes in tissue remodeling cytokine expression occurring in conjuction with inflammatory tissue changes. Antibody staining for upregulated cytokines suggests local production within the sinonasal mucosa. Further study is required to better understand the association between BMP, FGF and MMP regulation and tissue remodeling changes resulting from chronic inflammation.
PMCID: PMC3586207  PMID: 22294478
Tissue remodeling; chronic rhinosinusitis; murine model; MMP; BMP; FGF
18.  Bilateral Endoscopic Medial Maxillectomy for Bilateral Inverted Papilloma 
Case Reports in Otolaryngology  2012;2012:215847.
Inverted papilloma (IP) is a benign tumor of the nasal cavity and paranasal sinuses that is unilateral in most cases. Bilateral IP, involving both sides of the nasal cavity and sinuses, is extremely rare. This paper describes a large IP that filled in both sides of the nasal cavity and sinuses, mimicking association with malignancy. The tumor was successfully treated by bilateral endoscopic medial maxillectomy (EMM). The patient is without evidence of the disease 24 months after surgery. If preoperative diagnosis does not confirm the association with malignancy in IP, endoscopic sinus surgery (ESS) should be selected, and ESS, including EMM, is a good first choice of the treatment for IP.
PMCID: PMC3420519  PMID: 22953103
19.  Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity 
International Orthopaedics  2013;37(3):529-541.
The purpose of this study was to explore the effect of heparin on bone morphogenetic protein 6 (BMP6) osteogenic activity.
Western blot analysis was used to confirm the binding of BMP6 to heparin and to observe its effect on BMP6 signaling in C2C12-BRE-Luc myoblasts. Real-time RT-PCR was performed for the expression analysis of alkaline phosphatase (ALP) and osteocalcin (OC) in C2C12 myoblasts treated with BMP6 and heparin for 72 hours. Rat ectopic bone formation assay was performed to explore the effect of heparin on BMP6 osteogenic activity. Two weeks following implantation the implants were analysed morphologically and histologically. A mouse osteoporotic model was used to test the ability of BMP6 to improve the bone quality in vivo in the presence of heparin, followed by DEXA and μCT analyses. Blood coagulation was tested in rats previously treated with BMP6.
BMP6 specifically bound to heparin and induced Smad1/5/8 phosphorylation which was inhibited by heparin. After 48 and 72 hours of treatment, heparin inhibited BMP6-induced ALP and OC expression in C2C12 cells. Heparin dose dependently inhibited BMP6-induced new bone and cartilage formation in the rat ectopic bone formation assay, while in osteoporotic mice heparin inhibited the BMP6 potential to improve the bone quality as evidenced by decreased bone mineral density and trabecular bone parameters. Interestingly, BMP6 prevented the effect of heparin on the blood coagulation parameters.
The interaction of BMP6 with heparin might contribute to the heparin-induced osteoporosis and blood coagulation.
PMCID: PMC3580086  PMID: 23307015
20.  Benign Inverted Papilloma with Intracranial Extension: Prognostic Factors and Outcomes 
Skull Base Reports  2011;1(2):145-150.
We describe a case of benign inverted papilloma with intracranial extension treated with endoscopic resection combined with craniotomy. Intracranial involvement of inverted papilloma, in the absence of malignancy, is uncommon. We present an analysis of the literature identifying the characteristics and outcomes of benign intracranial inverted papilloma. PubMed database was searched using keywords intracranial, inverted or inverting, and papilloma. There are 17 reports of benign inverted papilloma with intracranial extension reported with a mean age of 49.2 years (range, 23 to 92 years), a female predominance, 22% of cases with an associated mucocele, and 60% recurrent disease. The most common sites of invasion are the frontal sinus or cribriform plate. The prognosis for benign intracranial inverted papilloma is dependent on the presence of dural invasion and the achievement of total resection. There are no reported recurrences after craniofacial resection with a mean follow-up of 7.9 years. Adjuvant radiation therapy has demonstrated benefit in cases of residual disease after resection. We expect that endoscopic resection, the standard treatment for sinonasal inverted papilloma, will be increasingly used in the presence of intracranial extension.
PMCID: PMC3743600  PMID: 23984218
Intracranial; inverted; inverting; Schneiderian; papilloma
21.  Effect of sonic hedgehog/β-TCP composites on bone healing within the critical-sized rat femoral defect 
The creation of entirely synthetically derived bone substitute materials which are as effective as autologous bone grafts is desirable. Osteogenesis involves the concerted action of several proteins within a signaling cascade. Hedgehog proteins act upstream of this cascade, inducing the expression of various bone morphogenetic proteins (BMPs) and promoting physiological bone healing. Therefore, the hypothesis that hedgehog signaling in bone defects improves bone healing more than BMP signaling alone was tested. Recombinant N-terminal sonic hedgehog protein (N-SHh), BMP-2 or a combination of the two was added to β-tricalcium phosphate (β-TCP) and 5-mm femoral midshaft defects in nude rats were filled with these composites. The defects were stabilized with mini-plates. After eight weeks, the animals were sacrificed and the femora were explanted. The radiological evaluation was followed by a three-point bending test and histological examination. BMP-2/β-TCP composites showed a trend of increased stiffness compared with the controls (β-TCP without protein). N-SHh/β-TCP composites had lower stiffness compared with the control group and the N-SHh/BMP-2/β-TCP composites also had lower average stiffness compared with the controls (all not significant). Histomorphometry, however, revealed abundant cartilage and bone core formation in the N-SHh-composite groups. The sum of the new cartilage and bone was highest in the combination group N-SHh/BMP-2 (not significant). The addition of N-SHh to bone substitute materials appears to delay bone healing at the applied concentration and observation time but also showed a trend for higher amounts of ossifying cartilage.
PMCID: PMC3627440  PMID: 23596469
bone substitute material; tricalcium phosphate; sonic hedgehog; bone morphogenetic protein-2; rat femur defect; three point bending test
22.  Effect of Phosphatidyl Inositol 3-Kinase, Extracellular Signal-Regulated Kinases 1/2, and p38 Mitogen-Activated Protein Kinase Inhibition on Osteogenic Differentiation of Muscle-Derived Stem Cells 
Tissue Engineering. Part A  2010;16(12):3647-3655.
Skeletal muscle-derived stem cells (MDSCs) can undergo osteogenesis when treated with bone morphogenetic proteins (BMPs), making them a potential cell source for bone tissue engineering. The signaling pathways that regulate BMP4-induced osteogenesis in MDSCs are not well understood, although they may provide a means to better regulate differentiation during bone regeneration. The objective of this study was to characterize the signaling pathways involved in the BMP4-induced osteogenesis of MDSCs. Cells were treated with BMP4 and specific inhibitors to the extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and phosphatidyl inositol 3-kinase (PI3K) pathways (PD98059, SB203580, and Ly294002, respectively). Cellular proliferation, expression of osteoblast-related genes, alkaline phosphatase (ALP) activity, and tissue mineralization were measured to determine the role of each pathway in the osteogenic differentiation of MDSCs. Inhibition of the ERK1/2 pathway increased ALP activity and mineralization, whereas inhibition of the p38 MAPK pathway decreased osteogenesis, suggesting opposing roles of these pathways in the BMP4-induced osteogenesis of MDSCs. Inhibition of the PI3K pathway significantly increased mineralization by MDSCs. These findings highlight the involvement of the ERK1/2, p38 MAPK, and PI3K pathways in opposing capacities in MDSC differentiation and warrant further investigation, as it may identify novel therapeutic targets for the development of stem cell-based therapies for bone tissue engineering.
PMCID: PMC2991210  PMID: 20617875
23.  Bone Morphogenetic Protein Type I Receptor Antagonists Decrease Growth and Induce Cell Death of Lung Cancer Cell Lines 
PLoS ONE  2013;8(4):e61256.
Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.
PMCID: PMC3625205  PMID: 23593444
24.  Schneiderian papillomas: Comparative review of exophytic, oncocytic, and inverted types 
Sinonasal papillomas are benign epithelial neoplasms arising from Schneiderian mucosa. The three subtypes, exophytic, oncocytic, and inverted (inverted papilloma [IP]), should be distinguished from one another histopathologically. This study (1) highlights the histopathological and clinical differences between the Schneiderian papilloma subtypes and (2) identifies clinical features that potentially predict papilloma subtypes.
A retrospective review was performed of patients with Schneiderian papillomas over an 11-year period.
Seventy patients with sinonasal papillomas who underwent sinus surgery were identified. There were 50 (71%) male and 20 (29%) female subjects diagnosed at an average age of 53 years (range, 13–80 years). Exophytic (n = 25), oncocytic (n = 9), and IP (n = 37) were identified. IP was associated with transformation into squamous cell carcinoma in three (8%) cases and dysplasia in three (8%) cases. Neither oncocytic nor exophytic subtypes were associated with dysplasia or malignancy. On multivariate analysis of potential predictors of papilloma subtype, history of chronic rhinosinusitis (CRS) and location of papilloma were significantly associated with papilloma subtype. Using classification and regression tree model, papilloma subtypes can be predicted based on presence or absence of CRS and papilloma location with nominal 82.4% accuracy.
The inverted and exophytic type are the most common sinonasal papillomas, with the inverted type having an 8% rate of malignant transformation in this study. In contrast, the oncocytic type was not associated with dysplasia or malignancy in our series despite reports in the literature indicating malignant potential. History of CRS and papilloma location can provide clues to the histological subtype, which is important for surgical planning and patient counseling.
PMCID: PMC3901443  PMID: 23883810
Cylindrical cell; exophytic; inverted; oncocytic; Schneiderian papillomas; sinonasal papillomas
25.  Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes 
BMC Medical Genomics  2011;4:80.
Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily of growth factors. They are known for their roles in regulation of osteogenesis and developmental processes and, in recent years, evidence has accumulated of their crucial functions in tumor biology. BMP4 and BMP7, in particular, have been implicated in breast cancer. However, little is known about BMP target genes in the context of tumor. We explored the effects of BMP4 and BMP7 treatment on global gene transcription in seven breast cancer cell lines during a 6-point time series, using a whole-genome oligo microarray. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and model based clustering of temporal data.
Both ligands had a strong effect on gene expression, although the response to BMP4 treatment was more pronounced. The cellular functions most strongly affected by BMP signaling were regulation of transcription and development. The observed transcriptional response, as well as its functional outcome, followed a temporal sequence, with regulation of gene expression and signal transduction leading to changes in metabolism and cell proliferation. Hierarchical clustering revealed distinct differences in the response of individual cell lines to BMPs, but also highlighted a synexpression group of genes for both ligands. Interestingly, the majority of the genes within these synexpression groups were shared by the two ligands, probably representing the core molecular responses common to BMP4 and BMP7 signaling pathways.
All in all, we show that BMP signaling has a remarkable effect on gene transcription in breast cancer cells and that the functions affected follow a logical temporal pattern. Our results also uncover components of the common cellular transcriptional response to BMP4 and BMP7. Most importantly, this study provides a list of potential novel BMP target genes relevant in breast cancer.
PMCID: PMC3229454  PMID: 22118688
bone morphogenetic protein; breast cancer; BMP4; BMP7; expression microarray

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