No description available.

No / Heterozygous germline defects in a gene encoding a type II receptor for bone morphogenetic proteins (BMPR-II) underlie the majority of inherited cases of the vascular disorder known as pulmonary arterial hypertension (PAH). However, the precise molecular consequences of PAH causing mutations on the function of the receptor complex remain unclear. We employed novel enzymatic and fluorescence activity based techniques to assess the impact of PAH mutations on pre-mRNA splicing, nonsense-mediated decay (NMD) and receptor complex interactions. We demonstrate that nonsense and frameshift mutations trigger NMD, providing further evidence that haplo-insufficiency is a major molecular consequence of disease-related BMPR2 mutations. We identified heterogeneous functional defects in BMPR-II activity, including impaired type I receptor phosphorylation, receptor interactions and altered receptor complex stoichiometry leading to perturbation of downstream signalling pathways. Importantly, these studies demonstrate that the intracellular domain of BMPR-II is both necessary and sufficient for receptor complex interaction. Finally and to address the potential for resolution of stoichiometric balance, we investigated an agent that promotes translational readthrough of a BMPR2 nonsense reporter construct without interfering with the NMD pathway. We propose that stoichiometric imbalance, due to either haplo-insufficiency or loss of optimal receptor-receptor interactions impairs BMPR-II mediated signalling in PAH. Taken together, these studies have identified an important target for early therapeutic intervention in familial PAH.

Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Autologous bone grafting is commonly used throughout the world. Autograft both fills the void and is bone inductive, housing the particular cells that are needed for bone regeneration. However, a regenerative complement to autograft is of great interest as the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of a limited volume of material. Two such regenerative products that utilise bone morphogenetic protein (BMP)-7 and -2 have been used for more than a decade clinically. Unfortunately, several side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery and use of supra physiological doses of the BMPs due to poor localisation and retention of the growth factor. The purpose of this thesis was to harness the strong inductive capacity of the BMP-2 by optimising the carrier of this bioactive protein, thereby minimising the side effects that are associated with the clinical products and facilitating safe and localised bone regeneration. We focused on an injectable hyaluronan-based carrier developed through polymer chemistry at the University of Uppsala. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident enzymes. Earlier studies have shown improved properties when adding hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that bone formation was enhanced when using nano-sized hydroxyapatite. In Paper II, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. We wished to further develop the carrier system, but were lacking an animal model with relatively high throughput, facilitated access, paired data, and we were also committed to the 3Rs of refinement, reduction, and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper III. In Paper IV, we sought to further optimise the biomaterial properties of the hydrogel through covalent bonding of bisphosphonates to the hyaluronan hydrogel. This resulted in exceptional retention of the growth factor BMP-2. In Paper V, SPECT/PET/µCT was combined as a tri-modal imaging method to allow visualisation of the biomaterial’s in situ action, in terms of drug retention, osteoblast activity and mineralisation. Finally, in Paper VI the correlation between existing in vitro results with in vivo outcomes was observed for an array of biomaterials. The study identified a surprisingly poor correlation between in vitro and in vivo assessment of biomaterials for osteogenesis.

A irradiação com laser em baixa intensidade (LLLI) e a proteína morfogenética óssea recombinante humana do tipo 2 (rhBMP-2) tem sido utilizadas para estimular a formação óssea. A LLLI estimula a proliferação de células precursoras de osteoblastos e a diferenciação celular e a rhBMP-2 recruta células osteoprogenitoras para a área de cicatrização óssea. Este estudo teve por objetivo avaliar os efeitos da LLLI e da rhBMP-2 sobre o processo de cicatrização óssea em calvária de ratas Wistar. Foram utilizados 42 animais e foram criados defeitos ósseos críticos nos ossos parietais. Os animais foram divididos em seis grupos de tratamento com 7 animais cada: Grupo 1- aplicação única de laser; Grupo 2 - 7 &mu;g de rhBMP- 2 pura; Grupo 3 - aplicação única de laser e 7 &mu;g de rhBMP-2 pura; Grupo 4 - 7 &mu;g de rhBMP-2 associada ao gel de monoleína; Grupo 5 - aplicação única de laser e 7 &mu;g de rhBMP-2 associada ao gel de monoleína e Grupo 6 - defeito ósseo crítico sem qualquer tipo de tratamento (grupo controle). Foi utilizado o laser diodo de arseneto de gálio-alumínio (AsGaAl, comprimento de onda de 780 nm, potência 60mW, área do feixe de 0,04 cm2, tempo de irradiação de 80 segundos, densidade de energia de 120 J/cm2, irradiância de 1,5 W/cm2). Após 15 dias as calvárias foram removidas para análise histomorfométrica. Após análise estatística, verificou-se que o Grupo 3 apresentou a maior quantidade de osso neoformado (37,89%) quando comparado aos outros grupos (p<0,05). As quantidades de osso neoformado nos defeitos ósseos dos Grupos 1 e 4 não foram estatisticamente significantes (24,00% e 24,75%, respectivamente), mas foram significantes quando comparadas aos valores dos outros Grupos (p<0,05). As quantidades de osso neoformado nos defeitos ósseos dos Grupos 2 e 5 não foram estatisticamente significantes (31,42% e 31,96%, respectivamente), mas foram significantes quando comparadas aos valores dos outros Grupos (p<0,05). O Grupo 6 apresentou neoformação óssea (14,10%) e esta foi estatisticamente significante quando comparada aos valores dos outros Grupos (p<0,05). Pode-se concluir que a LLLI administrada durante a cirurgia efetivamente acelerou a cicatrização de defeitos ósseos críticos preenchidos com rhBMP-2 pura, conseguindo melhores resultados quando comparadas com a aplicação isolada da LLLI ou da rhBMP-2. / Low-level laser irradiation (LLLI) and recombinant human bone morphogenetic protein type 2 (rhBMP-2) have been used to stimulate bone formation. LLLI stimulates proliferation of osteoblast precursor cells and cell differentiation and rhBMP-2 recruits osteoprogenitor cells to the bone healing area. This in study evaluated the effects of LLLI and rhBMP-2 on the bone healing process in calvaria of female Wistar rats. Critical bone defects were created in the parietal bone in 42 animals, and the animals were divided into six treatment groups with 7 animals: Group 1 - laser in a single application; Group 2- 7 &mu;g of pure rhBMP-2; Group 3 - laser in a single application and 7 &mu;g of pure rhBMP-2; Group 4 - 7 &mu;g of rhBMP-2 combined with monoolein gel, Group 5 - laser in a single application and 7 &mu;g of rhBMP-2 combined with monoolein gel; and Group 6 - critical bone defect controls. A gallium-aluminumarsenide diode laser was used (GaAlAs; wavelength 780 nm, output power 60mW, beam area 0.04 cm2, irradiation time 80 s, energy density 120 J/cm2, irradiance 1.5 W/cm2). After 15 days, the calvarial tissues were removed for histomorphometric analysis. Group 3 defects showed higher amounts of newly formed bone (37.89%) than the defects of all the other Groups (p<0.05). The amounts of new bone in defects of Groups 1 and 4 were not significantly different from each other (24.00% and 24.75%, respectively), but were significantly different from the amounts in the other Groups (p<0.05). The amounts of new bone in the defects of Groups 2 and 5 were not significantly different from each other (31.42% and 31.96%, respectively), but were significantly different from the amounts in the other Groups (p<0.05). Group 6 defects had 14.10% new bone formation, and this was significantly different from the amounts in the other Groups (p<0.05). It can be concluded that LLLI administered during surgery effectively accelerated healing of critical bone defects filled with pure rhBMP-2, achieving a better result than LLLI alone or the use of rhBMP-2 alone.

<p>The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.</p><p>This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.</p>

The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated. This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成3年2月1日 服部寿門氏の博士論文として提出された

Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Transplanting bone graft from one site in the patient to the site of fracture or bone void, i.e. autologous bone grafting is commonly used throughout the world. The transplanted bone not only fills voids, but is also bone inductive, housing the particular cells that are needed for bone regeneration. Nevertheless, a regenerative complement to autograft is of great interest and importance because the benefits from an off-the-shelf product with as good of healing capacity as autograft will circumvent most of the drawbacks with autograft. With a regenerative-medicine approach, the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of limited volume of material. Two such regenerative products that utilize bone morphogenetic protein 7 and 2 have been used for more than a decade in the clinic. However, some severe side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery, use of supra physiological doses of the BMPs due to poor localization and retention of the growth factors. The purpose of this thesis was to harness the strong inductive capability of the BMP-2 by optimizing the carrier of this bioactive protein, thereby minimizing the side effects that are associated with the clinical products and facilitating safe and localized bone regeneration at the desired site. We focused on an injectable hyaluronan-based carrier. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident hyaluronidase enzymes. Earlier studies have shown a more controlled release and improved mechanical properties when adding a weight of 25 percent of hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that the bone formation was enhanced when using nano-sized hydroxyapatite. We wished to further develop the carrier system but were lacking an animal model with high output and easy access. We also wanted to provide paired data and were committed to the 3 Rs of refinement, reduction and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper II. In Paper III, we characterized and optimized the handling properties of the carrier. In Paper IV, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. In Paper V, we sought to further optimize biomaterial properties of the hydrogel through covalently bonding of bisphosphonates to the hyaluronan hydrogel. The results demonstrated exceptional retention of the growth factor BMP-2. In Paper VI, the in vivo response related to the release of the growth factor was examined by combining a SPECT/PET/µCT imaging method to visualize both the retention of the drug, and the in-vivo response in terms of mineralization.

Made available in DSpace on 2015-07-22T20:50:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-01-26. Added 1 bitstream(s) on 2015-08-11T03:26:03Z : No. of bitstreams: 1 Publico-12529a.pdf: 1382817 bytes, checksum: 65bd98549521fbf2650836a170f9761e (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:03Z : No. of bitstreams: 2 Publico-12529a.pdf: 1382817 bytes, checksum: 65bd98549521fbf2650836a170f9761e (MD5) Publico-12529b.pdf: 1113563 bytes, checksum: 3261d75b2356f849d087c69443322b57 (MD5) / As BMPs, proteínas indutoras de crescimento ósseo, desde o início de sua utilização têm sido avaliadas em diferentes modelos experimentais objetivando determinar sua eficácia. Sabemos que algumas substâncias podem interferir positiva ou negativamente quando utilizadas de forma sistêmica ou local, associadas à BMP. Objetivo: Este estudo tem por objetivo avaliar as possíveis interferências da utilização de antibioticoterapia profilática pré e pós-operatória, utilizando-se como princípio ativo a cefazolina, aplicada a um modelo experimental em coelhos. Métodos: Foram utilizados dois grupos de coelhos fêmea, neozelandeses, submetidos à artrodese intertransversa da coluna lombar, segmento L5-L6, por via posterior. No primeiro grupo foi utilizado o enxerto autólogo associado ao biocomposto (BMP bovino, 1,0mg e hidroxiapatita, 9,0mg). No segundo grupo foi realizado o mesmo procedimento e utilizado o mesmo biocomposto, porém os animais foram submetidos a antibioticoterapia profilática com cefazolina iniciada duas horas antes e mantida por 24 horas após o término do procedimento. Os animais foram acompanhados por 15 semanas, isolados em cativeiro e avaliados diariamente por veterinário sob o ponto de vista clínico e neurológico, sendo posteriormente sacrificados e retiradas as peças cirúrgicas para serem submetidas à análise radiográfica e histológica. Resultados: Para o grupo 1, a quantidade e localização do material implantado variaram entre os indivíduos, porém, na maioria dos casos (6 amostras), a quantidade de partículas de osso homólogo era insignificante e estava dispersa ao longo do tecido mole que recobre o dorso da vértebra, circundado por tecido reacional com área de necrose. Nos demais casos as partículas com reabsorção preenchiam o reduzido espaço entre os processos transversos. Para o grupo 2, a quantidade do material e sua localização também variaram entre os indivíduos. Na maioria dos casos inúmeras partículas de osso mole preenchiam o espaço entre os processos laterais cuja neoformação óssea levou ao aprisionamento de algumas dessas partículas. Todos os casos exibiram formação em maior ou menor intensidade de tecido cartilaginoso na superfície dos processos transversos. A análise radiográfica mostrou em sua freqüência relativa maior freqüência de fusão completa para o grupo 2 quando comparado ao grupo 1. Conclusão: Do ponto de vista histológico para o modelo e período experimental analisado, inferimos que, embora nenhum dos tratamentos propostos tenha promovido o completo fusionamento das vértebras por tecido ósseo, a utilização de osso homólogo + BMP bovina, associada à aplicação de cefazolina, promoveu maior formação cartilaginosa e óssea com menor índice de rejeição do material enxertado na área doadora, quando comparada ao grupo sem associação de cefazolina. Do ponto de vista radiográfico, a análise relativa também demonstrou-se superior para o grupo onde foi utilizado cefazolina. / The BMPs, the inductive proteins of bone growth since the beginning of their use have been evaluated in different experimental models aiming to determine their efficacy. We know that some substances can interfere positively or negatively when used in a systemic way or places associated with the BMP. Objective: this study objective to evaluate the possible interferences of antibiotic-therapy by using the active principle of cefazolin in an experimental model with rabbits. Methods: Two groups of female New Zealand rabbits underwent a lumbar spine inter-transverse artrodesys of segment L5-L6 using posterior approach. An homolog bone graft associated with a bio-compound (bovine BMP, 1,0mg and hydroxiapatita, 9,0mg) was used in the first group. The same procedure and bio-compound were used in the second group. However the animals were submitted to a prophylactic antibiotic-therapy with cefazolin starting two hours before the procedure and maintained for 24 hours after surgery. The animals were analyzed for 15 weeks, isolated in captivity and daily evaluated by a veterinarian under the clinical and neurological views and then euthanized, being the surgical pieces removed and submitted to a radiological and histological analysis. Results: For the first group the quantity and location of the implanted material varied among the individuals. However in most of the cases, the quantity and particles of homolog bone was insignificant and disperse along the soft tissue that covers the posterior region of the vertebrae. In the other cases, the particles with reabsorvation filled the reduced space between the transversal processes. For the second group, the quantity of material and its location also varied among the individuals. In most of the cases, several particles of homolog bone filled the space between the lateral processes whose bone neo-formation led to a trapping of these particles. All the cases showed formation in a higher or lower intensity of the cartilaginous tissue in the surface of the transverse processes. The radiological analysis showed in its relative frequency a higher frequency of complete fusion for group 2 when compared to group 1. Conclusion: Under the histological view for the model and experimental period analyzed, we inferred that, despite the fact that none of the proposed treatments had promoted a complete fusion of the vertebraes per bone tissue, the use of homolog bone + bovine BMPs associated with the use of cefazolin promoted a higher cartilaginous and bone formation with lower incidence of rejection of the material grafted in the doer area when compared to the group without the association of cefazolin. Under the radiological view, the relative analysis also showed to be superior in the group where cefazolin was used as a prophylactic antibiotic. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2014-12-17T15:32:18Z (GMT). No. of bitstreams: 1 CyntiaCPC.pdf: 2470782 bytes, checksum: 4619c7ffcab85bffa54a732d30786d99 (MD5) Previous issue date: 2010-02-24 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Currently, bone morphogenetic proteins (BMPs) have effective participation in the growth of malignancies. Knowing that there are few studies involving BMPs and oral squamous cell carcinoma, this work constitutes an immunohistochemical study of BMP-2, BMPR IA and BMPR II in squamous cell carcinomas (SCC) of the lower lip relating to the clinical and pathological aspects of this lesion. The sample consisted of 40 cases of SCC of the lower lip, being 20 cases of SCC of the lower lip with regional metastasis and 20 cases without metastasis. We evaluated the intensity of expression (score 1 to mark absent / weak, score 2 for high ) and was found the percentage of labeled cells, where the score was 1 cases with 0 to 50% of positive cells, score 2 with 51 to 75% of positive cells, and score 3 more than 75% of positive cells. The sample comprised 72.5% of men with a mean age of 65.8 years, there was a predominance of stage II and 52.5% of the carcinomas were classified as low grade, being carcinoma with metastasis presenting most cases (70%) as carcinomas of high malignancy grade (p = 0.004). The largest number of cases of SCC of the lower lip that were in stages I / II (61, 9%) were classified as carcinomas of low grade malignancy and carcinomas in stages III / IV were classified as high-grade tumors (p = 0, 024). The BMP-2 showed strong intensity of immunostaining in 82.5%, BMPR-IA showed 55% of cases with an intensity of immunostaining absent / weak and BMPR-II showed 85% of cases with an intensity of immunostaining absent / weak. Only the protein BMPR-IA were significantly associated with all clinic-pathological parameters studied, metastasis (p <0.001), TNM (p <0.001) and histological grade of malignancy with (p = 0.028). The percentage of positive cells, all markers showed the highest number of cases with more than 75% of positive cells (score 3) and only BMPR-II showed statistical difference when related to the presence and absence of metastasis (p = 0.049 ). We conclude that there is disturbance in the BMP signaling pathway in EC-mediated lower lip and that high expression of BMP-2 associated with the expression of BMPR-IA and BMPR-II are associated with metastasis in carcinoma / Atualmente as prote?nas morfogen?ticas do osso (BMPs) t?m efetiva participa??o no crescimento de neoplasias malignas. Sabendo que s?o escassos os trabalhos envolvendo BMPs e o carcinoma epiderm?ide oral, este trabalho realizou um estudo imunoistoqu?mico da BMP-2, BMPR IA e BMPR II em carcinomas epiderm?ides (CE) de l?bio inferior relacionando com os aspectos clinico-patol?gicos desta les?o. A amostra constou de 40 casos de CE de l?bio inferior, sendo 20 casos de CE de l?bio inferior com met?stase linfonodal regional e 20 casos sem met?stase. A grada??o histol?gica de malignidade foi realizada no front invasivo da les?o. Foi avaliada a intensidade de express?o (escore 1 para marca??o ausente/ fraca e escore 2 para marca??o forte), bem como foi verificado a porcentagem de c?lulas positivas, onde o escore 1 era os casos com 0 a 50% das c?lulas positivas; escore 2 com 51 a 75% das c?lulas positivas; e escore 3 com mais de 75% das c?lulas positivas. A amostra foi composta por 72,5% de homens com a m?dia de idade de 65,8 anos, houve um predom?nio do est?gio II e 52,5% dos carcinomas foram classificados como de baixo grau, sendo os carcinomas com met?stase regional apresentando a maioria dos casos (70%) como carcinomas de alto grau de malignidade (p =0,004). O maior n?mero de casos de CE de l?bio inferior que estavam nos est?gios I/ II (61, 9%) foi classificado em carcinomas de baixo grau de malignidade e os carcinomas nos est?gios III/ IV foram classificados em alto grau de malignidade (p =0, 024). A BMP-2 apresentou intensidade da imunomarca??o forte em 82,5%, BMPR-IA observou-se 55% dos casos com intensidade de imunomarca??o ausente/ fraca e a BMPR-II revelou 85% dos casos com intensidade de imunomarca??o ausente/ fraca. Apenas a prote?na BMPR-IA apresentou associa??o estatisticamente significante com todos os par?metros clinico-patol?gicos estudados, met?stase (p<0,001), TNM (p<0,001) e grada??o histol?gica de malignidade com ( p=0,028). Quanto ? porcentagem de c?lulas positivas, todos os marcadores apresentaram o maior n?mero de casos com mais de 75% das c?lulas positivas (escore 3) e apenas a BMPR-II apresentou diferen?a estat?stica quando relacionada com a presen?a e aus?ncia de met?stase (p=0,049). Conclui-se que existe dist?rbio na via de sinaliza??o BMP-mediada no CE de l?bio inferior e que a alta express?o da BMP-2 associada com a express?o da BMPR-IA e BMPR-II est?o relacionadas com a met?stase neste carcinoma