The BMP Pathway and Its Inhibitors in the Skeleton
Créateur:
Lowery, Jonathan W. and Rosen, V.
Related Url Tesim:
https://www.ncbi.nlm.nih.gov/pubmed/30156494
La description:
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-? family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Identificateur:
10.1152/physrev.00028.2017
Type:
Article
Mot-clé:
bone development, Ligands, and Bone Morphogenetic Proteins
Genetic and functional studies indicate that common components of the bone morphogenetic protein (BMP) signaling pathway play critical roles in regulating vascular development in the embryo and in promoting vascular homeostasis and disease in the adult. However, discrepancies between in vitro and in vivo findings and distinct functional properties of the BMP signaling pathway in different vascular beds, have led to controversies in the field that have been difficult to reconcile. This review attempts to clarify some of these issues by providing an up to date overview of the biology and genetics of BMP signaling relevant to the intact vasculature.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Identificateur:
10.1016/j.cytogfr.2010.06.001
Type:
Article
Mot-clé:
Smad Proteins, Bone Morphogenetic Protein Receptors, Familial Primary Pulmonary Hypertension, and Neovascularization
The bone morphogenetic protein (BMP) type 2 receptor ligand, Bmp2, is upregulated in the peripheral pulmonary vasculature during hypoxia-induced pulmonary hypertension (PH). This contrasts with the expression of Bmp4, which is expressed in respiratory epithelia throughout the lung. Unlike heterozygous null Bmp4 mice (Bmp4(LacZ/+)), which are protected from the development of hypoxic PH, mice that are heterozygous null for Bmp2 (Bmp2(+/-)) develop more severe hypoxic PH than their wild-type littermates. This is associated with reduced endothelial nitric oxide synthase (eNOS) expression and activity in the pulmonary vasculature of hypoxic Bmp2(+/-) but not Bmp4(LacZ/+) mutant mice. Furthermore, exogenous BMP2 upregulates eNOS expression and activity in intrapulmonary artery and pulmonary endothelial cell preparations, indicating that eNOS is a target of Bmp2 signaling in the pulmonary vasculature. Together, these data demonstrate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH and suggest that the protective effects of Bmp2 are mediated by increasing eNOS expression and activity in the hypoxic pulmonary vasculature.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Identificateur:
10.1152/ajpregu.00534.2009
Type:
Article
Mot-clé:
Bone Morphogenetic Protein 4, Bone Morphogenetic Protein 2, Lac Operon, Pulmonary Circulation, and Nitric Oxide Synthase Type III
BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells Via Interaction With Acvr2b.
Créateur:
Cox, K., Katagiri, T., Kunikazu, T., Econimedes, A., Gamer, L., Rosen, V., Lowery, Jonathan W., and Kokabu, S
La description:
Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. However, the role of BMP in the maintenance of adult bone mass is not well understood. Targeted disruption of BMP3 in mice results in increased trabecular bone formation, whereas transgenic overexpression of BMP3 in skeletal cells leads to spontaneous fracture, consistent with BMP3 having a negative role in bone mass regulation. Here we investigate the importance of BMP3 as a mediator of BMP signaling in the adult skeleton. We find that osteoblasts (OBL) and osteocytes are the source of BMP3 in adult bone. Using in vitro cultures of primary bone marrow stromal cells, we show that overexpression of BMP3 suppresses OBL differentiation, whereas loss of BMP3 increases colony-forming unit fibroblasts and colony-forming unit OBL. The ability of BMP3 to affect OBL differentiation is due to its interaction with activin receptor type 2b (Acvr2b) because knockdown of endogenous Acvr2b in bone marrow stromal cells reduces the suppressive effect of BMP3 on OBL differentiation. These findings best fit a model in which BMP3, produced by mature bone cells, acts to reduce BMP signaling through Acvr2b in skeletal progenitor cells, limiting their differentiation to mature OBL. Our data further support the idea that endogenous BMPs have a physiological role in regulating adult bone mass.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Identificateur:
10.1210/me.2011-1168
Type:
Article
Mot-clé:
Inbred C57BL, Bone Morphogenetic Protein 3, RNA Interference, Signal Transduction, Gene Knock-In Techniques, Osteogenesis, Stromal Cells, Cell Differentiation, Activin Receptors, and Smad Proteins
BMPR-II is Dispensable for Formation of the Limb Skeleton.
Créateur:
Cox, K., Tsuji, K., Gamer, L.W., Capelo, L.P., Rosen, V., Lowery, Jonathan W., and Beppu, H.
La description:
Initiation of BMP signaling is dependent upon activation of Type I BMP receptor by constitutively active Type II BMP receptor. Three Type II BMP receptors have been identified; Acvr2a and Acvr2b serve as receptors for BMPs and for activin-like ligands whereas BMPR-II functions only as a BMP receptor. As BMP signaling is required for endochondral ossification and loss of either Acvr2a or Acvr2b is not associated with deficits in limb development, we hypothesized that BMPR-II would be essential for BMP signaling during skeletogenesis. We removed BMPR-II from early limb mesoderm by crossing BMPR-II floxed mice with those carrying the Prx1-Cre transgene. Mice lacking limb expression of BMPR-II have normal skeletons that could not be distinguished from control littermates. From these data, we conclude that BMPR-II is not required for endochondral ossification in the limb where loss of BMPR-II may be compensated by BMP utilization of Acvr2a and Acvr2b.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Type:
Article
Mot-clé:
Type II, Inbred C57BL, Signal Transduction, Bone Morphogenetic Protein Receptors, Osteogenesis, Gene Expression Regulation, Activin Receptors, Type I, and Sequence Deletion
Bone Morphogenetic Protein-Based Therapeutic Approaches
Créateur:
Lowery, Jonathan W. and Rosen, V.
Related Url Tesim:
https://www.ncbi.nlm.nih.gov/pubmed/28389444
La description:
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor (TGF)-? family of ligands and exert most of their effects through the canonical effectors Smad1, 5, and 8. Appropriate regulation of BMP signaling is critical for the development and homeostasis of numerous human organ systems. Aberrations in BMP pathways or their regulation are increasingly associated with diverse human pathologies, and there is an urgent and growing need to develop effective approaches to modulate BMP signaling in the clinic. In this review, we provide a wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction, outline the current strategies available to modulate BMP pathways, highlight emerging second-generation technologies, and postulate prospective avenues for future investigation.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Identificateur:
10.1101/cshperspect.a022327
Type:
Article
Mot-clé:
transforming growth factor and Bone morphogenetic proteins