RESUMEN
It has been previously reported that human embryonic fibroblasts and mouse embryonic fibroblasts can be converted into neuronal cells using chemical agents, along with forced expression specific transcriptional factors. However, the materials required for reprogramming in these approaches presents major technical difficulties and safety concerns. The current study investigated whether a cocktail of small molecules can convert human lung fibroblast cells into neurons. The small molecules valproic acid, CHIR99021, DMH1, Repsox, forskolin, Y27632 and SP600125 (VCHRFYS) were used to induce MRC5 cells into neuronal cells in vitro. Neuronal markers were analyzed by immunofluorescence staining. The gene profiles were analyzed by reverse transcriptionquantitative polymerase chain reaction. MRC5 is a human lung fibroblast cell line derived from normal lung tissue of a 14weekold male fetus. The results of the current study demonstrated that MRC5 fibroblasts can be directly converted into neuronal cells using a cocktail of seven small molecules (VCHRFYS), with a yield of ~90% Tuj1positive cells after 7 days of induction. Following a further maturation period, these chemically-induced neurons possessed neuronal morphology and expressed multiple neuronspecific genes. In conclusion, a cocktail of small molecules that can convert fibroblasts MRC5 cells into functional neurons without the exogenous genetic factors was identified, which has the potential to be useful in neurological disease therapy.
Asunto(s)
Fibroblastos/citología , Pulmón/citología , Neuronas/citología , Bibliotecas de Moléculas Pequeñas/farmacología , Línea Celular , Reprogramación Celular/efectos de los fármacos , Reprogramación Celular/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , FenotipoRESUMEN
Intestinal smooth muscle cells play a critical role in the remodeling of intestinal structure and functional adaptation after bowel resection. Recent studies have shown that supplementation of butyrate (Bu) contributes to the compensatory expansion of a muscular layer of the residual intestine in a rodent model of short-bowel syndrome (SBS). However, the underlying mechanism remains elusive. In this study, we found that the growth of human intestinal smooth muscle cells (HISMCs) was significantly stimulated by Bu via activation of Yes-Associated Protein (YAP). Incubation with 0.5 mM Bu induced a distinct proliferative effect on HISMCs, as indicated by the promotion of cell cycle progression and increased DNA replication. Notably, YAP silencing by RNA interference or its specific inhibitor significantly abolished the proliferative effect of Bu on HISMCs. Furthermore, Bu induced YAP expression and enhanced the translocation of YAP from the cytoplasm to the nucleus, which led to changes in the expression of mitogenesis genes, including TEAD1, TEAD4, CTGF, and Cyr61. These results provide evidence that Bu stimulates the growth of human intestinal muscle cells by activation of YAP, which may be a potential treatment for improving intestinal adaptation.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ácido Butírico/farmacología , Intestinos/citología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Fosfoproteínas/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fase G1/efectos de los fármacos , Humanos , Miocitos del Músculo Liso/efectos de los fármacos , Fase S/efectos de los fármacos , Factores de Transcripción , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Proteínas Señalizadoras YAPRESUMEN
Enterocyte apoptosis induced by lipid emulsions is a key cause of intestinal atrophy under total parenteral nutrition (TPN) support, and our previous work demonstrated that olive oil lipid emulsion (OOLE) could induce enterocyte apoptosis via CUGBP, Elav-like family member 1 (CELF1)/ apoptosis-inducing factor (AIF) pathway. As TPN-associated complications are partially related to choline deficiency, we aimed to address whether choline supplementation could attenuate OOLE-induced enterocyte apoptosis. Herein we present evidence that supplementary choline exhibits protective effect against OOLE-induced enterocyte apoptosis both in vivo and in vitro. In a rat model of TPN, substantial reduction in apoptotic rate along with decreased expression of CELF1 was observed when supplementary choline was added to OOLE. In cultured Caco-2 cells, supplementary choline attenuated OOLE-induced apoptosis and mitochondria dysfunction by suppressing CELF1/AIF pathway. Compared to OOLE alone, the expression of CELF1 and AIF was significantly decreased by supplementary choline, whereas the expression of Bcl-2 was evidently increased. No obvious alterations were observed in Bax expression and caspase-3 activation. Mechanistically, supplementary choline repressed the expression of CELF1 by increasing the recruitment of CELF1 mRNA to processing bodies, thus resulting in suppression of its protein translation. Taken together, our data suggest that supplementary choline exhibits effective protection against OOLE-induced enterocyte apoptosis, and thus, it has the potential to be used for the prevention and treatment of TPN-induced intestinal atrophy.
Asunto(s)
Factor Inductor de la Apoptosis/genética , Atrofia/prevención & control , Proteínas CELF1/genética , Deficiencia de Colina/prevención & control , Colina/administración & dosificación , Aceite de Oliva/efectos adversos , Nutrición Parenteral Total/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Factor Inductor de la Apoptosis/metabolismo , Atrofia/inducido químicamente , Atrofia/genética , Atrofia/fisiopatología , Proteínas CELF1/metabolismo , Células CACO-2 , Caspasa 3/genética , Caspasa 3/metabolismo , Deficiencia de Colina/genética , Deficiencia de Colina/fisiopatología , Modelos Animales de Enfermedad , Emulsiones , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Enterocitos/patología , Regulación de la Expresión Génica , Humanos , Intestinos/efectos de los fármacos , Intestinos/fisiopatología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Aceite de Oliva/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND & AIMS: Our previous studies have provided evidence that p38 mitogen-activated protein kinase (MAPK) is involved in total parenteral nutrition (TPN)-associated complications, but its exact effects and mechanisms have not been fully understood. This study aimed to evaluate the roles of p38 MAPK inhibitor SB203580 in the TPN-induced loss of intestinal barrier function and liver disease. METHODS: A rodent model of TPN was used to analyze the roles of SB203580 in TPN-associated complications.Intestinal barrier function was evaluated by transepithelial electrical resistance (TER) and paracellular permeability in Caco-2 cells. The palmitic acid (PA) was used to induce hepatic lipoapoptosis in vitro. The lipoapoptosis was detected using Caspase-3/7 and lipid staining. RESULTS: In the present study, we showed that SB203580 treatment significantly suppressed TPN-mediated intestinal permeability in rats. SB203580 treatment significantly inhibited IL-1ß-induced an increase in tight junction permeability of Caco-2 cells via repressing the p38/ATF-2 signaling. Unexpectedly, SB203580 treatment enhanced hepatic lipoapoptosis in the model of TPN. Palmitic acid (PA)-induced hepatic lipoapoptosis in human liver cells was significantly augmented by the SB203580 treatment. CONCLUSIONS: We demonstrate that the p38 MAPK inhibitor SB203508 ameliorates intestinal barrier function but promotes hepatic lipoapoptosis in model of TPN.
Asunto(s)
Apoptosis/efectos de los fármacos , Imidazoles/farmacología , Mucosa Intestinal/efectos de los fármacos , Piridinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Factor de Transcripción Activador 2/antagonistas & inhibidores , Factor de Transcripción Activador 2/genética , Factor de Transcripción Activador 2/metabolismo , Animales , Células CACO-2 , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Interleucina-1beta/farmacología , Mucosa Intestinal/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Modelos Animales , Ácido Palmítico/toxicidad , Nutrición Parenteral Total , Permeabilidad/efectos de los fármacos , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
BACKGROUND AND AIMS: Parenterally-administered lipid emulsion (LE) is a key cause of enterocyte apoptosis under total parenteral nutrition, yet the pathogenesis has not been fully understood. CUGBP, Elav-like family member 1 (CELF1) has been recently identified as a crucial modulator of apoptosis, and thus this study sought to investigate its role in the LE-induced apoptosis in vitro. METHODS: Caco-2 cells were used as an in vitro model. The cells were treated with varying LEs derived from soybean oil, olive oil or fish oil, and changes in the apoptosis and CELF1 expression were assessed. Rescue study was performed using transient knockdown of CELF1 with specific siRNA prior to LE treatment. Regulation of CELF1 by LE treatment was studied using quantitative real-time PCR and Western blotting. RESULTS: All the LEs up-regulated CELF1expression and induced apoptosis, but only olive oil-supplemented lipid emulsion (OOLE)-induced apoptosis was attenuated by depletion of CELF1. Up-regulation of apoptosis-inducing factor (AIF) was involved in OOLE-induced CELF1 dependent apoptosis. The protein expression of CELF1 was up-regulated by OOLE in a dose- and time-dependent manner, but the mRNA expression of CELF1 was unchanged. Analysis by polysomal profiling and nascent protein synthesis revealed that the regulation of CELF1 by OOLE treatment was mediated by directly accelerating its protein translation. CONCLUSION: OOLE-induces apoptosis in Caco-2 cells partially through up-regulation of CELF1.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas CELF1/metabolismo , Emulsiones/química , Aceite de Oliva/farmacología , Factor Inductor de la Apoptosis/metabolismo , Proteínas CELF1/antagonistas & inhibidores , Proteínas CELF1/genética , Células CACO-2 , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Emulsiones/farmacología , Aceites de Pescado/química , Humanos , Aceite de Oliva/química , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Aceite de Soja/química , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Intestinal failure (IF)-associated liver disease (IFALD), as a major complication, contributes to significant morbidity in pediatric IF patients. However, the pathogenesis of IFALD is still uncertain. We here investigate the roles of bile acid (BA) dysmetabolism in the unclear pathogenesis of IFALD. It found that the histological evidence of pediatric IF patients exhibited liver injury, which was characterized by liver bile duct proliferation, inflammatory infiltration, hepatocyte apoptosis and different stages of fibrosis. The BA compositions were altered in serum and liver of pediatric IF patients, as reflected by a primary BA dominant composition. In IF patients, the serum FGF19 levels decreased significantly, and were conversely correlated with ileal inflammation grades (r = -0.50, p < 0.05). In ileum, the inflammation grades were inversely associated with farnesoid X receptor (FXR) expression (r = -0.55, p < 0.05). In liver, the expression of induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1) increased evidently. In conclusion, ileum inflammation decreases FXR expression corresponding to reduce serum FGF19 concentration, along with increased hepatic bile acid synthesis, leading to liver damages in IF patients.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Enfermedades Intestinales/patología , Hepatopatías/patología , Ácidos y Sales Biliares/sangre , Preescolar , Colesterol 7-alfa-Hidroxilasa/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Enfermedades del Íleon/patología , Lactante , Interleucina-6 , Enfermedades Intestinales/complicaciones , Hígado/metabolismo , Hepatopatías/etiología , Hepatopatías/metabolismo , Masculino , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR-124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-α. Further studies showed that miR-124 could directly target the 3'-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-α production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation.
Asunto(s)
Acetilcolinesterasa/metabolismo , Regulación hacia Abajo/genética , Enfermedades Intestinales/genética , Activación de Macrófagos/genética , MicroARNs/genética , Factor de Transcripción STAT3/metabolismo , Regiones no Traducidas 3'/genética , Animales , Secuencia de Bases , Niño , Sulfato de Dextran , Humanos , Interleucina-6/metabolismo , Enfermedades Intestinales/patología , Mucosa Intestinal/metabolismo , Intestinos/patología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Fosforilación , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND AND AIMS: Elevated intestinal permeability of lipopolysaccharide (LPS) is a major complication for patients with parenteral nutrition (PN), but the pathogenesis is poorly understood. Intestinal P-glycoprotein (P-gp) is one of the efflux transporters that contribute to restricting the permeability of lipopolysaccharide via transcellular route. P-gp expression may be regulated by PN ingredients, and thus this study sought to investigate the effect of PN on the expression of P-gp and to elucidate the underlying mechanism in vitro. METHODS: Caco-2 cells were treated with PN ingredients. Changes in P-gp expression and function were determined and the role of ERK-FOXO 3a pathway was studied. Transport studies of FITC-lipopolysaccharide (FITC-LPS) across Caco-2 cell monolayers were also performed. RESULTS: Among PN ingredients, soybean oil-based lipid emulsion (SOLE) exhibited significant inhibitory effect on P-gp expression and function. This regulation was mediated via activation of ERK pathway with subsequent nuclear exclusion of FOXO 3a. Importantly, P-gp participated in antagonizing the permeation of FITC-LPS (apical to basolateral) across Caco-2 cell monolayers. SOLE significantly increased the permeability of FITC-LPS (apical to basolateral), which was associated with impaired P-gp function. CONCLUSIONS: The expression and function of intestinal P-gp is suppressed by SOLE in vitro.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Proteína Forkhead Box O3/genética , Lipopolisacáridos/farmacología , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Aceite de Soja/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transporte Biológico , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Emulsiones , Fluoresceína-5-Isotiocianato/química , Colorantes Fluorescentes/química , Proteína Forkhead Box O3/metabolismo , Regulación de la Expresión Génica , Humanos , Lipopolisacáridos/agonistas , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismoRESUMEN
The cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) have been implicated as important mediators of the inflammatory reaction in patients with intestinal inflammation. The present study was designed to investigate the roles of these cytokines on mucosal barrier function in a mouse model of acute colitis with using anti-cytokine strategies. Mice received 3% dextran sulfate sodium (DSS) in their drinking water for 7days showed morphological alteration of mucosa and increase of intestinal permeability. Administration of IL-6 monoclonal antibody (mAb) or TNF-α mAb significantly attenuated intestinal permeability. IL-6 mAb and TNF-α mAb treatment also effectively suppressed the expression of claudin-2 and myosin light chain kinase (MLCK). Taken together, we indicated that anti-IL-6 and anti-TNF-α therapy prevent intestinal permeability induced by intestinal inflammation.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Colitis/metabolismo , Sulfato de Dextran/toxicidad , Interleucina-6/antagonistas & inhibidores , Mucosa Intestinal/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Colitis/inducido químicamente , Colitis/patología , Interleucina-6/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones , Permeabilidad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIM: To investigate the disruptions of interstitial cells of Cajal (ICC) in the remaining bowel in rats after massive small bowel resection (mSBR). METHODS: Thirty male Sprague-Dawley rats fitting entry criteria were divided randomly into three experimental groups (n = 10 each): Group A rats underwent bowel transection and re-anastomosis (sham) and tissue samples were harvested at day 7 post-surgery. Group B and C rats underwent 80% small bowel resection with tissue harvested from Group B rats at day 7 post-surgery, and from Group C rats at day 14 post-surgery. The distribution of ICC at the site of the residual small bowel was evaluated by immunohistochemical analysis of small intestine samples. The ultrastructural changes of ICC in the remnant ileum of model rats 7 and 14 d after mSBR were analyzed by transmission electron microscopy. Intracellular recordings of slow wave oscillations were used to evaluate electrical pacemaking. The protein expression of c-kit, ICC phenotypic markers, and membrane-bound stem cell factor (mSCF) in intestinal smooth muscle of each group were detected by Western blotting. RESULTS: After mSBR, immunohistochemical analysis indicated that the number of c-kit-positive cells was dramatically decreased in Group B rats compared with sham tissues. Significant ultrastructural changes in ICC with associated smooth muscle hypertrophy were also observed. Disordered spontaneous rhythmic contractions with reduced amplitude (8.5 ± 1.4 mV vs 24.8 ± 1.3 mV, P = 0.037) and increased slow wave frequency (39.5 ± 2.1 cycles/min vs 33.0 ± 1.3 cycles/min, P = 0.044) were found in the residual intestinal smooth muscle 7 d post mSBR. The contractile function and electrical activity of intestinal circular smooth muscle returned to normal levels at 14 d post mSBR (amplitude, 14.9 ± 1.6 mV vs 24.8 ± 1.3 mV; frequency, 30.7 ± 1.7 cycles/min vs 33.0 ± 1.3 cycles/min). The expression of Mscf and c-kit protein was decreased at 7 d (P = 0.026), but gradually returned to normal levels at 14 d. The ICC and associated neural networks were disrupted, which was associated with the phenotype alterations of ICC. CONCLUSION: Massive small bowel resection in rats triggered damage to ICC networks and decreased the number of ICC leading to disordered intestinal rhythmicity. The mSCF/c-kit signaling pathway plays a role in the regulation and maintenance of ICC phenotypes.
Asunto(s)
Células Intersticiales de Cajal/patología , Intestino Delgado/patología , Intestino Delgado/cirugía , Animales , Biomarcadores/metabolismo , Western Blotting , Motilidad Gastrointestinal , Hipertrofia , Inmunohistoquímica , Células Intersticiales de Cajal/metabolismo , Células Intersticiales de Cajal/ultraestructura , Intestino Delgado/inervación , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatología , Masculino , Microscopía Electrónica de Transmisión , Músculo Liso/patología , Músculo Liso/fisiopatología , Fenotipo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factor de Células Madre/metabolismo , Factores de TiempoRESUMEN
AIM: To investigate the ultrastructural location of midkine (MK) in nucleolus and function corresponding to its location. METHODS: To investigate the ultrastructural location of MK in nucleolus with immunoelectronic microscopy. To study the role that MK plays in ribosomal biogenesis by real-time PCR. The effect of MK on anti-apoptotic activity of HepG2 cells was studied with FITC-conjugated annexin V and propidium iodide PI double staining through FACS assay. RESULTS: MK mainly localized in the granular component (GC), dense fibrillar component (DFC) and the border between the DFC and fibrillar center (FC). The production of 45S precursor rRNA level was decreased significantly in the presence of MK antisense oligonucleotide in the HepG2 cells. Furthermore, it was found that exogenous MK could protect HepG2 from apoptosis significantly. CONCLUSION: MK was constitutively translocated to the nucleolus of HepG2 cells, where it accumulated and mostly distributed at DFC, GC components and at the region between FC and DFC, MK played an important role in rRNA transcription, ribosome biogenesis, and cell proliferation in HepG2 cells. MK might serve as a molecular target for therapeutic intervention of human carcinomas.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Nucléolo Celular/metabolismo , Neoplasias Hepáticas/metabolismo , Factores de Crecimiento Nervioso/metabolismo , ARN Ribosómico/metabolismo , Transcripción Genética , Transporte Activo de Núcleo Celular , Apoptosis , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/ultraestructura , Línea Celular Tumoral , Nucléolo Celular/ultraestructura , Proliferación Celular , Separación Celular , Citometría de Flujo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/ultraestructura , Microscopía Inmunoelectrónica , Midkina , Factores de Crecimiento Nervioso/genética , Oligonucleótidos Antisentido/metabolismo , Reacción en Cadena de la PolimerasaRESUMEN
The vacuolar H(+)-ATPase (V-ATPase) is a universal component of eukaryotic organisms, which is present in both intracellular compartments and the plasma membrane. In the latter, its proton-pumping action creates the low intravacuolar pH, benefiting many processes such as, membrane trafficking, protein degradation, renal acidification, bone resorption, and tumor metastasis. In this article, we briefly summarize recent studies on the essential and diverse roles of mammalian V-ATPase and their medical applications, with a special emphasis on identification and use of V-ATPase inhibitors.
Asunto(s)
ATPasas de Translocación de Protón Vacuolares/metabolismo , Animales , Enfermedades Óseas/enzimología , Enfermedades Óseas/terapia , Humanos , ATPasas de Translocación de Protón Vacuolares/químicaRESUMEN
Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the transforming growth factor-beta superfamily. It has been demonstrated that BMPs had been involved in the regulation of cell proliferation, survival, differentiation and apoptosis. However, their hallmark ability is that play a pivotal role in inducing bone, cartilage, ligament, and tendon formation at both heterotopic and orthotopic sites. In this review, we mainly concentrate on BMP structure, function, molecular signaling and potential medical application.