Role Of Bone Morphogenetic Proteins Research Articles

Progastrin Stimulates Colonic Cell Proliferation via CCK2R- and β-Arrestin–Dependent Suppression of BMP2

Progastrin stimulates colonic mucosal proliferation and carcinogenesis through the cholecystokinin 2 receptor (CCK2R)-partly by increasing the number of colonic progenitor cells. However, little is known about the mechanisms by which progastrin stimulates colonic cell proliferation. We investigated the role of bone morphogenetic proteins (BMPs) in progastrin induction of colonic cell proliferation via CCK2R. We performed microarray analysis to compare changes in gene expression in the colonic mucosa of mice that express a human progastrin transgene, gastrin knockout mice, and C57BL/6 mice (controls); the effects of progastrin were also determined on in vitro colonic crypt cultures from cholecystokinin 2 receptor knockout and wild-type mice. Human colorectal and gastric cancer cells that expressed CCK2R were incubated with progastrin or Bmp2; levels of β-arrestin 1 and 2 were knocked down using small interfering RNAs. Cells were analyzed for progastrin binding, proliferation, changes in gene expression, and symmetric cell division. The BMP pathway was down-regulated in the colons of human progastrin mice compared with controls. Progastrin suppressed transcription of Bmp2 through a pathway that required CCK2R and was mediated by β-arrestin 1 and 2. In mouse colonic epithelial cells, down-regulation of Bmp2 led to decreased phosphorylation of Smads1/5/8 and suppression of inhibitor of DNA binding 4. In human gastric and colorectal cancer cell lines, CCK2R was necessary and sufficient for progastrin binding and induction of proliferation; these effects were blocked when cells were incubated with recombinant Bmp2. Incubation with progastrin increased the number of CD44(+), bromodeoxyuridine+, and NUMB(+) cells, indicating an increase in symmetric divisions of putative cancer stem cells. Progastrin stimulates proliferation in colons of mice and cultured human cells via CCK2R- and β-arrestin 1 and 2-dependent suppression of Bmp2 signaling. This process promotes symmetric cell division.

Bone morphogenetic protein 9 overexpression reduces osteosarcoma cell migration and invasion.

Transforming growth factor-β (TGF-β) is known to promote tumor migration and invasion. Bone morphogenetic proteins (BMPs) are members of the TGF-β family expressed in a variety of human carcinoma cell lines. The role of bone morphogenetic protein 9 (BMP9), the most powerful osteogenic factor, in osteosarcoma (OS) progression has not been fully clarified. The expression of BMP9 and its receptors in OS cell lines was analyzed by RT-PCR. We found that BMP9 and its receptors were expressed in OS cell lines. We further investigated the influence of BMP9 on the biological behaviors of OS cells. BMP9 overexpression in the OS cell lines 143B and MG63 inhibited in vitro cell migration and invasion. We further investigated the expression of a panel of cancer-related genes and found that BMP9 overexpression increased the phosphorylation of Smad1/5/8 proteins, increased the expression of ID1, and reduced the expression and activity of matrix metalloproteinase 9 (MMP9) in OS cells. BMP9 silencing induced the opposite effects. We also found that BMP9 may not affect the chemokine (C-X-C motif) ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis to regulate the invasiveness and metastatic capacity of OS cells. Interestingly, CXCR4 was expressed in both 143B and MG63 cells, while CXCL12 was only detected in MG63 cells. Taken together, we hypothesize that BMP9 inhibits the migration and invasiveness of OS cells through a Smad-dependent pathway by downregulating the expression and activity of MMP9.

Bi‐directional roles of bone morphogenetic proteins in cancer: Another molecular Jekyll and Hyde?

Bone morphogenetic proteins (BMPs) are multi-functional cytokines, which belong to the transforming growth factor-β (TGF-β) family. In some cancer tissues, aberrant expression of various BMP signal components has been detected. Here, we describe the divergent roles of BMPs during the progression of cancer. BMPs exhibit various effects on both cancer cells and on tumor microenvironments. BMPs inhibit the proliferation of cancer cells, with some exceptions. BMPs also induce the differentiation of certain cancer stem cells, and attenuate their aggressiveness. In parallel, BMPs play a critical role in the regulation of tumor angiogenesis and the metastasis of cancer cells. Some mouse xenograft models have revealed that cancer metastases are prevented by the inhibition of BMP signaling. Together, these findings imply that BMPs function as both suppressors and promoters of tumors in a context dependent manner. The bi-directional characteristics of BMPs in cancer are similar to those of TGF-β, which was previously described as a molecular 'Jekyll and Hyde.'

Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium

Formation of the periodontium begins following onset of tooth-root formation in a coordinated manner after birth. Dental follicle progenitor cells are thought to form the cementum, alveolar bone and Sharpey's fibers of the periodontal ligament (PDL). However, little is known about the regulatory morphogens that control differentiation and function of these progenitor cells, as well as the progenitor cells involved in crown and root formation. We investigated the role of bone morphogenetic protein-2 (Bmp2) in these processes by the conditional removal of the Bmp2 gene using the Sp7-Cre-EGFP mouse model. Sp7-Cre-EGFP first becomes active at E18 in the first molar, with robust Cre activity at postnatal day 0 (P0), followed by Cre activity in the second molar, which occurs after P0. There is robust Cre activity in the periodontium and third molars by 2 weeks of age. When the Bmp2 gene is removed from Sp7+ (Osterix+) cells, major defects are noted in root, cellular cementum and periodontium formation. First, there are major cell autonomous defects in root-odontoblast terminal differentiation. Second, there are major alterations in formation of the PDLs and cellular cementum, correlated with decreased nuclear factor IC (Nfic), periostin and α-SMA+ cells. Third, there is a failure to produce vascular endothelial growth factor A (VEGF-A) in the periodontium and the pulp leading to decreased formation of the microvascular and associated candidate stem cells in the Bmp2-cKOSp7-Cre-EGFP. Fourth, ameloblast function and enamel formation are indirectly altered in the Bmp2-cKOSp7-Cre-EGFP. These data demonstrate that the Bmp2 gene has complex roles in postnatal tooth development and periodontium formation.

Basolateral BMP Signaling in Polarized Epithelial Cells

Bone morphogenetic proteins (BMPs) regulate various biological processes, mostly mediated by cells of mesenchymal origin. However, the roles of BMPs in epithelial cells are poorly understood. Here, we demonstrate that, in polarized epithelial cells, BMP signals are transmitted from BMP receptor complexes exclusively localized at the basolateral surface of the cell membrane. In addition, basolateral stimulation with BMP increased expression of components of tight junctions and enhanced the transepithelial resistance (TER), counteracting reduction of TER by treatment with TGF-β or an anti-tumor drug. We conclude that BMPs maintain epithelial polarity via intracellular signaling from basolaterally localized BMP receptors.

Bone Morphogenetic Protein 4 Supports the Initial Differentiation of Hen (Gallus gallus) Granulosa Cells

In the hen ovary, selection of a follicle into the preovulatory hierarchy occurs from a small cohort of prehierarchal (6-8 mm) follicles. Prior to follicle selection the granulosa layer remains in an undifferentiated state despite elevated follicle-stimulating hormone receptor (FSHR) expression. The present studies describe a role for bone morphogenetic protein 4 (BMP4) in supporting FSHR mRNA expression in granulosa cells from prehierarchal follicles and promoting differentiation at follicle selection. Culture of undifferentiated granulosa cells in culture medium alone resulted in a significant decline in levels of FSHR mRNA (by ~80% compared to freshly collected cells). By comparison, granulosa cultured with BMP4 (10-100 ng/ml) maintained FSHR and expression at approximately in vivo levels. Because both granulosa and theca tissues from prehierarchal follicles express BMP4, it is suggested that BMP4 acts in a paracrine and/or autocrine fashion to support elevated FSHR expression prior to follicle selection. Granulosa cells cultured with BMP4 for 24 h also initiated FSH-induced cAMP production and indirectly initiated anti-Mullerian hormone (AMH), CYP11A, and STAR expression plus progesterone production. However, pretreatment with the BMP antagonist NOGGIN or the mitogen-activated protein kinase (MAPK) agonist transforming growth factor alpha attenuated or blocked each action promoted by BMP4. We conclude that prior to and immediately after selection, BMP4 serves to support FSHR expression within the granulosa layer, yet prior to selection, multiple factors (including inhibitory MAPK signaling, AMH, and BMP antagonists) can modulate FSHR expression and suppress FSH-mediated cell signaling to prevent granulosa cell differentiation prior to follicle selection.

Bone morphogenetic proteins regulate differentiation of human promyelocytic leukemia cells

We investigated the role of bone morphogenetic proteins (BMPs) in suppression of all-trans retinoic acid (ATRA)-mediated differentiation of leukemic promyelocytes. In NB4 and HL60 cell lines, BMPs reduced the percentage of differentiated cells, and suppressed PU.1 and C/EBPε gene expression induced by ATRA. BMP and ATRA synergized in the induction of ID genes, causing suppression of differentiation. In primary acute promyelocytic leukemia bone-marrow samples, positive correlation of PML/RARα and negative of RARα with the expression of BMP-4, BMP-6 and ID genes were found. We concluded that BMPs may have oncogenic properties and mediate ATRA resistance by a mechanism that involves ID genes.

Noggin Attenuates Cerulein-Induced Acute Pancreatitis and Impaired Autophagy

To investigate the role of bone morphogenetic protein (BMP) signaling in acute pancreatitis (AP) by administration of noggin, an endogenous BMP antagonist, in a cerulein-induced AP model. Acute pancreatitis was induced by 9 hourly intraperitoneal injections of cerulein (50 μg/kg). Control mice received phosphate-buffered saline injections. In a separate group, noggin (0.5 mg/kg) was given intraperitoneally at 1 hour before and 2, 4, and 6 hours after AP induction. The mice were euthanized at 1 hour after completion of AP induction. The blood samples and the pancreas were harvested for analysis. Isolated pancreatic acini from normal mice and AR42J cells were treated with BMP2 and cerulein. AR42J cells were also treated with noggin. Phosphorylation of Smad1/5/8 was measured. Bone morphogenetic protein signaling was up-regulated in AP mouse pancreas. Bone morphogenetic protein 2 and cerulein-induced phosphorylation of Smad1/5/8 in the acinar cells in vitro, which was blocked by noggin. Noggin administration in vivo attenuated AP induction, decreased vacuole formation in acinar cells, blocked LC3-II levels, and partially restored Beclin-1 and lysosomal-associated membrane protein 2 levels. Bone morphogenetic protein signaling seems to promote AP induction and autophagy, as suggested by our study showing that noggin ameliorates AP and partially restores autophagic homeostasis.

Role of BMPs in the regulation of sclerostin as revealed by an epigenetic modifier of human bone cells

Sclerostin, encoded by the SOST gene, is specifically expressed by osteocytes. However osteoblasts bear a heavily methylated SOST promoter and therefore do not express SOST. Thus, studying the regulation of human SOST is challenged by the absence of human osteocytic cell lines. Herein, we explore the feasibility of using the induction of SOST expression in osteoblasts by a demethylating agent to study the mechanisms underlying SOST transcription, and specifically, the influence of bone morphogenetic proteins (BMPs).Microarray analysis and quantitative PCR showed that AzadC up-regulated the expression of several BMPs, including BMP-2, BMP-4 and BMP-6, as well as several BMP downstream targets. Recombinant BMP-2 increased the transcriptional activity of the SOST promoter cloned into a reporter vector. Likewise, exposing cells transfected with the vector to AzadC also resulted in increased transcription. On the other hand, inhibition of the canonical BMP signaling blunted the effect of AzadC on SOST.These results show that the AzadC-induced demethylation of the SOST promoter in human osteoblastic cells may be a valuable tool to study the regulation of SOST expression. As a proof of concept, it allowed us to demonstrate that BMPs stimulate SOST expression by a mechanism involving BMPR1A receptors and downstream Smad-dependent pathways.

Emerging pathogenic mechanisms in human myxomatous mitral valve: lessons from past and novel data

Myxomatous mitral valve is one of the most common heart valves diseases in human and has been well characterized at a functional and morphological level. Diseased valves are thickened as a result of extracellular matrix remodeling and proteoglycans accumulation accompanied by the disruption of the stratified structures of the leaflets. Global transcriptomic analysis was used as a start-up to investigate potential pathogenic mechanisms involved in the development of the human idiopathic myxomatous mitral valve, which have been elusive for many years. These prospective analyses have highlighted the potential role of apparently unrelated molecules in myxomatous mitral valve such as members of the transforming growth factor-β superfamily, aggrecanases of the "a disintegrin and metalloprotease with thrombospondin repeats I" family, and a weakening of the protection against oxidative stress. We have integrated, in this review, recent transcriptomic data from our laboratory [A. Hulin, C.F. Deroanne, C.A. Lambert, B. Dumont, V. Castronovo, J.O. Defraigne, et al. Metallothionein-dependent up-regulation of TGF-beta2 participates in the remodelling of the myxomatous mitral valve. Cardiovasc Res 2012;93:480-489] and from the publication of Sainger et al. [R. Sainger, J.B. Grau, E. Branchetti, P. Poggio, W.F. Seefried, B.C. Field, et al. Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation. J Cell Physiol 2012;227:2595-2604] with existing literature and information issued from the study of monogenic syndromes and animal models. Understanding cellular alterations and molecular mechanisms involved in myxomatous mitral valve should help at identifying relevant targets for future effective pharmacological therapy to prevent or reduce its progression.

Abstract 18829: Inhibiting Bone Morphogenetic Protein Signaling Reduces Diabetes-Associated Non-Alcoholic Fatty Liver Disease Independent of Plasma Lipid Levels

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with diabetes and atherosclerotic heart disease and its presence predicts worse cardiovascular outcomes. However, the mechanisms responsible for NAFLD remain unclear and no targeted medical therapy exists. Given the essential role for bone morphogenetic protein (BMP) signaling in the development of atherosclerosis and related inflammation, we hypothesized that BMP signaling is upregulated in livers of diabetic mice (db/db) known to develop NAFLD and that pharmacologic inhibition of BMP signaling may reduce fatty liver disease. Methods: Livers from adult male wild-type (WT) and db/db mice were harvested to quantify Smad 1/5 phosphorylation and Id1 gene expression (markers of BMP signaling). Diabetic mice were treated with either vehicle or the small molecule BMP type I receptor inhibitor, LDN-193189 (LDN, 3 mg/kg twice daily IP), for 28 days. Plasma samples were collected, and livers were harvested for biochemical and histological examination. Hepatic fat content was estimated using colorimetric intensity quantification of hematoxylin & eosin stains. Results: Smad 1/5 phosphorylation and Id1 mRNA levels were 2.5- and 3.0-fold greater in livers of db/db mice than in WT mice (P=0.003 and 0.006, respectively; n=8 per group). Treatment of db/db mice with LDN decreased liver Smad 1/5 phosphorylation and Id1 mRNA levels associated with a 49% reduction in hepatic fat accumulation (P=0.017; see Figure). Furthermore, plasma alanine aminotransferase levels were less in LDN-treated mice than in vehicle-treated mice (mean ± SEM 194 ± 68 vs. 583 ± 153 U/L, n=7 per group, P=0.048); however, there was no difference in plasma cholesterol or triglyceride levels. Conclusions: Increased BMP signaling contributes to the development of NAFLD in a diabetic mouse model, independent of plasma lipid levels. Pharmacologic BMP inhibition may represent a novel therapy for NAFLD.

BMPS and Liver: More Questions than Answers

Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and were first discovered as potent bone homeostasis regulators for their ability to induce endochondral bone formation, ectopic bone formation and fracture repair. A preeminent role of BMP signaling in developmental control of cell type specification, differentiation and organogenesis is also well established. More recently, a role for BMPs in adult tissue homeostasis has started being revealed. Thus, new studies show that BMPs regulate many cellular processes such as proliferation, apoptosis, differentiation and migration in many tissues and organs. As a consequence, dysregulation of BMP activity can have pathological consequences, and there is mounting evidence for the involvement of BMPs in different human diseases. In this review, we have focused on summarizing the present knowledge on the relevance of BMPs in liver physiology and pathophysiology, from the well-recognized role in liver development to the emerging contribution to the function and dysfunction of the adult liver. While no doubts seem to rise about the regulatory activities of BMPs on metabolic pathways in the liver, potential pro- and anti-fibrogenic and tumorigenic actions will likely be a matter of debate during coming years. Collectively, the work here presented provides the basis to consider BMPs as potential targets of intervention in liver diseases.

Osteoporosis genetics: year 2011 in review

Increased rates of osteoporotic fractures represent a worldwide phenomenon, which result from a progressing aging in the population around the world and creating socioeconomic problems. This review will focus mostly on human genetic studies identifying genomic regions, genes and mutations associated with osteoporosis (bone mineral density (BMD) and bone loss) and related fractures, which were published during 2011. Although multiple genome-wide association studies (GWAS) were performed to date, the genetic cause of osteoporosis and fractures has not yet been found, and only a small fraction of high heritability of bone mass was successfully explained. GWAS is a successful tool to initially define and prioritize specific chromosomal regions showing associations with the desired traits or diseases. Following the initial discovery and replication, targeted sequencing is needed in order to detect those rare variants which GWAS does not reveal by design. Recent GWAS findings for BMD included WNT16 and MEF2C. The role of bone morphogenetic proteins in fracture healing has been explored by several groups, and new single-nucleotide polymorphisms present in genes such as NOGGIN and SMAD6 were found to be associated with a greater risk of fracture non-union. Finding new candidate genes, and mutations associated with BMD and fractures, also provided new biological connections. Thus, candidates for molecular link between bone metabolism and lactation (for example, RAP1A gene), as well as possible pleiotropic effects for bone and muscle (ACTN3 gene) were suggested. The focus of contemporary studies seems to move toward whole-genome sequencing, epigenetic and functional genomics strategies to find causal variants for osteoporosis.

Emerging Role of Bone Morphogenetic Proteins as a Context Dependent Pro-Angiogenic Cue

Bone morphogenetic proteins (BMPs), members of the transforming growth factor Β (TGF-Β) superfamily, are multifunctional secreted growth factors that are essential for coordinating complex developmental processes. Recent advances using genetic and molecular approaches have recognized a previously underappreciated angiogenic role for BMP signaling during vascular development and vascular disease. Compelling evidence includes the discovery of mutations in BMP signaling components that have been found in patients with human hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH). A comprehensive review of in vivo and in vitro studies has revealed that the angiogenic response to BMP signaling is context and ligand dependent. This review provides details on these studies as the field moves towards BMP-mediated therapeutic intervention of human vascular diseases. Keywords: Bone Morphogenetic Protein, BMP signaling, angiogenesis, vascular development, HHT.

The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation

The bone morphogenetic proteins (BMPs) are a group of powerful morphogens that are critical for development of the nervous system. The effects of BMP signaling on neural stem cells are myriad and dynamic, changing with each stage of development. During early development inhibition of BMP signaling differentiates neuroectoderm from ectoderm, and BMP signaling helps to specify neural crest. Thus modulation of BMP signaling underlies formation of both the central and peripheral nervous systems. BMPs secreted from dorsal structures then form a gradient which helps pattern the dorsal-ventral axis of the developing spinal cord and brain. During forebrain development BMPs sequentially induce neurogenesis and then astrogliogenesis and participate in neurite outgrowth from immature neurons. BMP signaling also plays a critical role in maintaining adult neural stem cell niches in the subventricular zone (SVZ) and subgranular zone (SGZ). BMPs are able to exert such diverse effects through closely regulated temporospatial expression and interaction with other signaling pathways.

Activation of BMP-Smad1/5/8 Signaling Promotes Survival of Retinal Ganglion Cells after Damage In Vivo

While the essential role of bone morphogenetic protein (BMP) signaling in nervous system development is well established, its function in the adult CNS is poorly understood. We investigated the role of BMP signaling in the adult mouse retina following damage in vivo. Intravitreal injection of N-Methyl-D-aspartic acid (NMDA) induced extensive retinal ganglion cell death by 2 days. During this period, BMP2, -4 and -7 were upregulated, leading to phosphorylation of the downstream effector, Smad1/5/8 in the inner retina, including in retinal ganglion cells. Expression of Inhibitor of differentiation 1 (Id1; a known BMP-Smad1/5/8 target) was also upregulated in the retina. This activation of BMP-Smad1/5/8 signaling was also observed following light damage, suggesting that it is a general response to retinal injuries. Co-injection of BMP inhibitors with NMDA effectively blocked the damage-induced BMP-Smad1/5/8 activation and led to further cell death of retinal ganglion cells, when compared with NMDA injection alone. Moreover, treatment of the retina with exogenous BMP4 along with NMDA damage led to a significant rescue of retinal ganglion cells. These data demonstrate that BMP-Smad1/5/8 signaling is neuroprotective for retinal ganglion cells after damage, and suggest that stimulation of this pathway can serve as a potential target for neuroprotective therapies in retinal ganglion cell diseases, such as glaucoma.

Prostate Cancer Cells and Bone Stromal Cells Mutually Interact with Each Other through Bone Morphogenetic Protein-mediated Signals

Functional interactions between cancer cells and the bone microenvironment contribute to the development of bone metastasis. Although the bone metastasis of prostate cancer is characterized by increased ossification, the molecular mechanisms involved in this process are not fully understood. Here, the roles of bone morphogenetic proteins (BMPs) in the interactions between prostate cancer cells and bone stromal cells were investigated. In human prostate cancer LNCaP cells, BMP-4 induced the production of Sonic hedgehog (SHH) through a Smad-dependent pathway. In mouse stromal MC3T3-E1 cells, SHH up-regulated the expression of activin receptor IIB (ActR-IIB) and Smad1, which in turn enhanced BMP-responsive reporter activities in these cells. The combined stimulation with BMP-4 and SHH of MC3T3-E1 cells cooperatively induced the expression of osteoblastic markers, including alkaline phosphatase, bone sialoprotein, collagen type II α1, and osteocalcin. When MC3T3-E1 cells and LNCaP cells were co-cultured, the osteoblastic differentiation of MC3T3-E1 cells, which was induced by BMP-4, was accelerated by SHH from LNCaP cells. Furthermore, LNCaP cells and BMP-4 cooperatively induced the production of growth factors, including fibroblast growth factor (FGF)-2 and epidermal growth factor (EGF) in MC3T3-E1 cells, and these may promote the proliferation of LNCaP cells. Taken together, our findings suggest that BMPs provide favorable circumstances for the survival of prostate cancer cells and the differentiation of bone stromal cells in the bone microenvironment, possibly leading to the osteoblastic metastasis of prostate cancer.

BMP-2 Up-Regulates PTEN Expression and Induces Apoptosis of Pulmonary Artery Smooth Muscle Cells under Hypoxia

AimTo investigate the role of bone morphogenetic protein 2 (BMP-2) in regulation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) and apoptosis of pulmonary artery smooth muscle cells (PASMCs) under hypoxia.MethodsNormal human PASMCs were cultured in growth medium (GM) and treated with BMP-2 from 5–80 ng/ml under hypoxia (5% CO2+94% N2+1% O2) for 72 hours. Gene expression of PTEN, AKT-1 and AKT-2 were determined by quantitative RT-PCR (QRT-PCR). Protein expression levels of PTEN, AKT and phosph-AKT (pAKT) were determined. Apoptosis of PASMCs were determined by measuring activities of caspases-3, -8 and -9. siRNA-smad-4, bpV(HOpic) (PTEN inhibitor) and GW9662 (PPARγ antagonist) were used to determine the signalling pathways.ResultsProliferation of PASMCs showed dose dependence of BMP-2, the lowest proliferation rate was achieved at 60 ng/ml concentration under hypoxia (82.2±2.8%). BMP-2 increased PTEN gene expression level, while AKT-1 and AKT-2 did not change. Consistently, the PTEN protein expression also showed dose dependence of BMP-2. AKT activity significantly reduced in BMP-2 treated PASMCs. Increased activities of caspase-3, -8 and -9 of PASMCs were found after cultured with BMP-2. PTEN expression remained unchanged when Smad-4 expression was inhibited by siRNA-Smad-4. bpV(HOpic) and GW9662 (PPARγ inhibitor) inhibited PTEN protein expression and recovered PASMCs proliferation rate.ConclusionBMP-2 increased PTEN expression under hypoxia in a dose dependent pattern. BMP-2 reduced AKT activity and increased caspase activity of PASMCs under hypoxia. The increased PTEN expression may be mediated through PPARγ signalling pathway, instead of BMP/Smad signalling pathway.

The Role of BMPs in Bone Anabolism and their Potential Targets SOST and DKK1

Bone morphogenetic proteins (BMPs) were discovered in 1965 as potent inducers of ectopic bone formation when implanted subcutaneously. BMP2, BMP4, BMP6, and BMP7 are osteoinductive, and BMP2 and BMP7 are currently approved for clinical applications such as bone fracture healing and spine surgery. Although BMPs’ role in bone formation is well known, the current clinical data supporting their effectiveness are not robust, possibly in part because BMPs affect bone resorption as well. BMPs can reduce bone mass by inducing osteoclastogenesis via the RANKL-OPG pathway, which is a critical regulator of osteoclasts by osteoblasts. BMPs have both bone anabolic and catabolic effects by affecting multiple cell types in bone such as mesenchymal cells, chondrocytes, osteoblasts, osteoclasts, and endothelial cells. We recently generated an osteoblast-targeted deletion of BMP signaling using a Cre-loxP strategy and found that BMP signaling in osteoblasts can inhibit Wnt signaling through the Wnt inhibitors DKK1 and SOST. Loss-of-function of either DKK1 or SOST, which are downstream targets of BMPs, causes a high bone mass phenotype in humans and mice, suggesting an importance of DKK1 and SOST for bone mass regulation. There are many bone anabolic effectors that control bone mass such as BMPs, PTH, and Wnt inhibitors. This article will focus on BMPs’ effects on bone anabolism and propose a potential network of the bone mass mediators BMPs, PTH, and SOST. We believe it is important to understand this network to guide the clinical application of bone anabolic agents.

The Role of BMPs in Bone Anabolism and their Potential Targets SOST and DKK1

Bone morphogenetic proteins (BMPs) were discovered in 1965 as potent inducers of ectopic bone formation when implanted subcutaneously. BMP2, BMP4, BMP6, and BMP7 are osteoinductive, and BMP2 and BMP7 are currently approved for clinical applications such as bone fracture healing and spine surgery. Although BMPs' role in bone formation is well known, the current clinical data supporting their effectiveness are not robust, possibly in part because BMPs affect bone resorption as well. BMPs can reduce bone mass by inducing osteoclastogenesis via the RANKL-OPG pathway, which is a critical regulator of osteoclasts by osteoblasts. BMPs have both bone anabolic and catabolic effects by affecting multiple cell types in bone such as mesenchymal cells, chondrocytes, osteoblasts, osteoclasts, and endothelial cells. We recently generated an osteoblast-targeted deletion of BMP signaling using a Cre-loxP strategy and found that BMP signaling in osteoblasts can inhibit Wnt signaling through the Wnt inhibitors DKK1 and SOST. Loss-of-function of either DKK1 or SOST, which are downstream targets of BMPs, causes a high bone mass phenotype in humans and mice, suggesting an importance of DKK1 and SOST for bone mass regulation. There are many bone anabolic effectors that control bone mass such as BMPs, PTH, and Wnt inhibitors. This article will focus on BMPs' effects on bone anabolism and propose a potential network of the bone mass mediators BMPs, PTH, and SOST. We believe it is important to understand this network to guide the clinical application of bone anabolic agents.