The BMP pathway could curb cachexia

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

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EGR2, IGF1 and IL6 Expression Are Elevated in the Intervertebral Disc of Patients Suffering from Diffuse Idiopathic Skeletal Hyperostosis (DISH) Compared to Degenerative or Trauma Discs

Applied Sciences ◽

10.3390/app11094072 ◽

2021 ◽

Vol 11 (9) ◽

pp. 4072

Author(s):

Benjamin Gantenbein ◽

Rahel D. May ◽

Paola Bermudez-Lekerika ◽

Katharina A. C. Oswald ◽

Lorin M. Benneker ◽

...

Keyword(s):

Growth Factor ◽

Nucleus Pulposus ◽

Transforming Growth Factor ◽

Diffuse Idiopathic Skeletal Hyperostosis ◽

Transforming Growth Factor Β ◽

Intervertebral Discs ◽

Serum Marker ◽

Ectopic Ossification ◽

Disc Cells ◽

Bmp Pathway

Diffuse idiopathic skeletal hyperostosis (DISH) is characterised by ectopic ossification along the anterior spine and the outer intervertebral discs (IVD). However, the centre of the IVD, i.e., the nucleus pulposus, always remains unaffected, which could be due to the inhibition of the bone morphogenetic protein (BMP) pathway. In this study, we investigated the transcriptome for the BMP pathway of DISH-IVD cells versus disc cells of traumatic or degenerative discs. The disc cells originated from nucleus pulposus (NP), annulus fibrosus (AF) and from cartilaginous endplate (CEP) tissue. Here, ninety genes of the transforming growth factor β-BMP signalling pathway were screened by qPCR. Furthermore, the protein expression of genes of interest was further investigated by immune-staining and semi-quantitative microscopy. IVDs of three DISH patients were tested against three control patients (same disc level and similar age). Early Growth Response 2 (EGR2) and Interleukin 6 (IL6) were both significantly up-regulated in DISH-IVD cells compared to controls (12.8 ± 7.6-fold and 54.0 ± 46.5-fold, respectively, means ± SEM). Furthermore, Insulin-like Growth Factor 1 (IGF1) tended to be up-regulated in DISH-IVD donors, i.e., 174.13 ± 120.6-fold. IGF1 was already known as a serum marker for DISH and other rheumatoid diseases and is confirmed here to play a possible key role in DISH-IVD.

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Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells

Carcinogenesis ◽

10.1093/carcin/bgs233 ◽

2012 ◽

Vol 33 (10) ◽

pp. 1985-1992 ◽

Cited By ~ 38

Author(s):

V. Camilo ◽

R. Barros ◽

S. Sousa ◽

A. M. Magalhaes ◽

T. Lopes ◽

...

Keyword(s):

Helicobacter Pylori ◽

Sox2 Expression ◽

Gastric Cells ◽

Bmp Pathway

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Coordinated Regulation of Axonal Microtubule Organization and Transport by Drosophila Neurexin and BMP Pathway

Scientific Reports ◽

10.1038/s41598-018-35618-7 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 4

Author(s):

Swati Banerjee ◽

Maeveen Riordan

Keyword(s):

Microtubule Organization ◽

Bmp Pathway ◽

Coordinated Regulation

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Cardiac looping and the vertebrate left-right axis: antagonism of left-sided Vg1 activity by a right-sided ALK2-dependent BMP pathway

Development ◽

10.1242/dev.126.23.5195 ◽

1999 ◽

Vol 126 (23) ◽

pp. 5195-5205 ◽

Cited By ~ 5

Author(s):

A.F. Ramsdell ◽

H.J. Yost

Keyword(s):

Signaling Pathway ◽

Expression Patterns ◽

Ectopic Expression ◽

Xenopus Embryo ◽

Receptor Expression ◽

Heart Tube ◽

Cardiac Morphogenesis ◽

Heart Looping ◽

Bmp Pathway ◽

The Right

The rightward looping of the primary heart tube is dependent upon upstream patterning events that establish the vertebrate left-right axis. In Xenopus, a left-sided Vg1 signaling pathway has been implicated in instructing cells to adopt a ‘left-sided identity’; however, it is not known whether ‘right-sided identity’ is acquired by a default pathway or by antagonism of Vg1 signaling. Here, we propose that an antagonistic, BMP/ALK2/Smad-mediated signaling pathway is active on the right side of the Xenopus embryo. Truncated ALK2 receptor expression on the right side of the blastula elicits heart reversals and altered nodal expression. Consistent with these findings, constitutively active ALK2 (CA-ALK2) receptor expression on the left side of the blastula also elicits heart reversals and altered nodal expression. Coexpression of CA-ALK2 with mature Vg1 ligand results in predominantly left-sided nodal expression patterns and normal heart looping, demonstrating that the ALK2 pathway can ‘rescue’ left-right reversals that otherwise occur following right-sided misexpression of mature Vg1 ligand alone. Results with chimeric precursor proteins indicate that the mature domain of BMP ligands can mimic the ability of the ALK2 signaling pathway to antagonize the Vg1 pathway. Consistent with the observed antagonism between BMP and Vg1 ligands, left-sided ectopic expression of Xolloid results in heart reversals. Moreover, ectopic expression of Smad1 or Smad7 identified two downstream modulators of the BMP/ALK2 signaling pathway that also can regulate cardiac orientation. Collectively, these results define a BMP/ALK2-mediated pathway on the right side of the Xenopus embryo and, moreover, suggest that left-right patterning preceding cardiac morphogenesis involves the activation of two distinct and antagonistic, left- and right-sided TGF(beta)-related signaling pathways.

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Biphasic activation of the BMP pathway patterns the Drosophila embryonic dorsal region

Development ◽

10.1242/dev.128.6.965 ◽

2001 ◽

Vol 128 (6) ◽

pp. 965-972 ◽

Cited By ~ 3

Author(s):

R. Dorfman ◽

B.Z. Shilo

Keyword(s):

Inhibitory Activity ◽

Early Phase ◽

Drosophila Embryo ◽

Activation Pattern ◽

Wild Type ◽

Germ Band ◽

Dorsal Region ◽

Bmp Pathway ◽

Simultaneous Activation ◽

Blastoderm Stage

The BMP pathway patterns the dorsal region of the Drosophila embryo. Using an antibody recognizing phosphorylated Mad (pMad), we followed signaling directly. In wild-type embryos, a biphasic activation pattern is observed. At the cellular blastoderm stage high pMad levels are detected only in the dorsal-most cell rows that give rise to amnioserosa. This accumulation of pMad requires the ligand Screw (Scw), the Short gastrulation (Sog) protein, and cleavage of their complex by Tolloid (Tld). When the inhibitory activity of Sog is removed, Mad phosphorylation is expanded. In spite of the uniform expression of Scw, pMad expansion is restricted to the dorsal domain of the embryo where Dpp is expressed. This demonstrates that Mad phosphorylation requires simultaneous activation by Scw and Dpp. Indeed, the early pMad pattern is abolished when either the Scw receptor Saxophone (Sax), the Dpp receptor Thickveins (Tkv), or Dpp are removed. After germ band extension, a uniform accumulation of pMad is observed in the entire dorsal domain of the embryo, with a sharp border at the junction with the neuroectoderm. From this stage onward, activation by Scw is no longer required, and Dpp suffices to induce high levels of pMad. In these subsequent phases pMad accumulates normally in the presence of ectopic Sog, in contrast to the early phase, indicating that Sog is only capable of blocking activation by Scw and not by Dpp.

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Abstract 19602: Characterization of Tgfβ/BMP-axis in Multiple Animal Models of PH

Circulation ◽

10.1161/circ.132.suppl_3.19602 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Chris Happé ◽

Nina Rol ◽

Denielli Da Silva Goncalves Bos ◽

Cathelijne van der Bruggen ◽

Anton Vonk-Noordegraaf ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Animal Models ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Downstream Signaling ◽

Protein Levels ◽

Morphogenetic Protein ◽

Cardiac Adaptation ◽

Bmp Pathway ◽

Β Receptor

Introduction: Mutations in the bone morphogenetic protein recptor type 2 (BMPR2) comprise a large portion of familial Pulmonary Arterial Hypertension (PAH) cases. The transforming growth factor-β (TGF-β)/BMP-axis in PAH has been of interest, which is hypothesized to favor TGF-β signaling due to defective BMPR2 signaling, consequently leading to pro-proliferative signaling within the lung. In addition, it has been proposed that the BMPRII mutations might affect cardiac adaptation. To date none of the available animal models have been fully characterized with regard to the TGF-β/BMP pathway. This study assessed the lung and heart TGF-β/BMP-axis in multiple rat animal models of pulmonary hypertension to ensure translational capability. Methods: Heart and lung TGF-β/BMP-axis was assessed by qPCR, western blot and immunofluorescence in the the monocrotaline (MCT), Sugen-hypoxia (SuHx), Sugen-Pneumonectomy (SuPnx) and Pulmonary artery banding model (PAB) and compared to control and PAH patient tissues. Circulating ligands, TGF-β receptor (TGFβR) type 1 and 2 and BMPR2, and canonical downstream signaling (Smad2/3, Smad1/5/8, and transcription factors) were investigated. Results: BMPR2 was down-regulated at both transcription and protein levels in the lung of all PH animal models (p<0.05). Transcription of pulmonary TGFβR1 and -2 were increased in the SuPNx-model, compared to control (P<0.001). In both SuHx and SuPnx models an increase in protein Smad2/3 expression was observed by immunofluorescence implying overactivation of TGF-β signaling. Cardiac TGFβR1 was decreased in PAB model, compared to control (P<0.05), while TGFβR2 was decreased in both the MCT and PAB model. Conclusion: Early indications reveal differences between several pulmonary hypertension animal models, with regard to the TGF-β/BMP pathway. Additional analysis is needed to fully characterize the regulation of TGF-β and BMP in the rat models.

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