Comparison of newly developed anti-bone morphogenetic protein 4 llama-derived antibodies with commercially available BMP4 inhibitors

Calpe, Silvia; Correia, Ana C. P.; Sancho-Serra, Maria del Carmen; Krishnadath, Kausilia K.

doi:10.1080/19420862.2016.1158380

Cited by 15 publications

(14 citation statements)

References 59 publications

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“…This is the case of engineered BMP2 and BMP7 that are resistant to Noggin inhibition . Furthermore, neutralizing antibodies that affect ligand–receptor interactions by binding to ligands have been produced (Figure ). Another strategy has been the development of antibodies that bind to secreted ligand‐binding proteins thereby promoting BMP receptor signaling (Figure ).…”

Section: Bmpr Signalingmentioning

confidence: 99%

Bone morphogenetic protein receptor signal transduction in human disease

Gomez‐Puerto

Iyengar

Vinuesa

et al. 2018

The Journal of Pathology

172

137

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Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor‐regulated SMAD1, 5, and 8 (also termed R‐SMADs). Activated R‐SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and, besides the canonical SMAD pathway, BMP‐receptor activation can also induce non‐SMAD signaling. Each step in the pathway is fine‐tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand‐binding proteins that sequester the ligand from interacting with receptors. Accessory co‐receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and musculoskeletal diseases and cancer. We describe pharmacological tools to interrogate the function of BMP receptor signaling in specific biological processes and focus on how these agents can be used as drugs to inhibit or activate the function of the receptor, thereby normalizing dysregulated BMP signaling. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Bmpr Signalingmentioning

confidence: 99%

Bone morphogenetic protein receptor signal transduction in human disease

Gomez‐Puerto

Iyengar

Vinuesa

et al. 2018

The Journal of Pathology

172

137

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“…Identification of the BMP members that may stimulate the first steps of enthesis ossification in SpA could provide promising therapeutic targets. Disease and tissue context probably regulate very finely BMP signaling so that increasing both specificity and effectiveness of BMP-targeting strategies could be mandatory [67]. Nevertheless, our results settled the interest of investigating BMP pathways in SpA patients.…”

Section: Discussionmentioning

confidence: 77%

Enhanced BMP-2/BMP-4 ratio in patients with peripheral spondyloarthritis and in cytokine- and stretch-stimulated mouse chondrocytes

et al. 2020

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Background Excessive bone formation in the entheses is one of the features of peripheral spondyloarthritis (SpA). Complex pathological mechanisms connecting inflammation, mechanical stress, and ossification are probably involved. We focused on bone morphogenetic protein (BMP)-2, -4, and -7 as possible mediators of this process. Methods BMP-2, -4, and -7 concentration was measured by ELISA in synovial fluids (SFs) of SpA (n = 56) and osteoarthritic (n = 21) patients. Mouse organotypic ankle cultures were challenged by a pro-inflammatory cocktail. Mouse primary chondrocytes, osteoblasts, or tenocytes were treated with TNF-α, interleukin (IL)-17, or IL-22 and/or subjected to cyclic stretch, or with recombinant BMP-2 or -4. Results In SpA SFs, if BMP-7 was barely detectable, BMP-2 concentration was higher and BMP-4 was lower than in osteoarthritic samples, so that BMP-2/BMP-4 ratio augmented 6.5 folds (p < 0.001). In SpA patients, TNF-α, IL-6, and IL-17 levels correlated this ratio (n = 21). Bmp-2/Bmp-4 ratio was similarly enhanced by cytokine treatment in explant and cell cultures, at mRNA level. In particular, simultaneous application of TNF-α and cyclical stretch induced a 30-fold increase of the Bmp-2/Bmp-4 ratio in chondrocytes (p = 0.027). Blockade of prostaglandin E2 and IL-6 production had almost no effect on the stretch-induced regulation of Bmp-2 or -4. Osteoinductive effects of BMP-4, and to a lesser extend BMP-2, were identified on cultured chondrocytes and tenocytes. Conclusions Our results first settle that BMP factors are locally deregulated in the SpA joint. An unexpected decrease in BMP-4 could be associated to an increase in BMP-2, possibly in response to mechanical and/or cytokine stimulations.

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“…Noggin is a non-selective BMP inhibitor, and given its pleiotropic effects, it is not suitable for systemic treatment in humans. Recently, we developed novel highly selective inhibitors against BMP2 and BMP4 [ 29 , 30 ]. Future studies will demonstrate the efficacy and safety of these novel anti-BMP therapies and their use for treatment of BE.…”

Section: Discussionmentioning

confidence: 99%

Novel In Vivo Mouse Cryoablation Model to Explore Unique Therapeutic Approaches for Premalignant Columnar Lesions

Correia

Straub

Calpe

et al. 2021

MPs

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Patients with epithelial metaplasias have an increased risk of developing malignancies. In Barrett’s esophagus, neo-columnar epithelium develops proximal to the squamous-columnar junction (SCJ) in the esophagus as the result of prolonged exposure to bile and acid reflux. Patients require lifetime periodic surveillance, due to lack of effective eradication therapies. The shortage of innovative treatment options is mostly attributable to the paucity of adequate in vivo models of neo-columnar epithelium regeneration. This protocol describes the generation of a cryoablation model to study regeneration of neo-epithelia at the SCJ. Cryoablation of the columnar and squamous mucosa at the SCJ was achieved through local application of liquid N2O in wild-type and reporter mice in combination with acid suppression. Acid suppression alone, showed restoration of the SCJ with normal histological features of both the neo-columnar and neo-squamous epithelium within 14 days. As a proof of principle, mice were treated with mNoggin, an inhibitor of bone morphogenetic proteins (BMPs), which are involved in the development of columnar epithelia. Local application of mNoggin to the ablated area at the SCJ significantly reduced the development of the neo-columnar mucosa. Although this model does not faithfully recapitulate the exact characteristics of Barrett’s esophagus, it is a well-suited tool to study the mechanisms of therapeutic inhibition of neo-columnar regeneration. It therefore represents an efficient and easy platform to test novel pharmacological therapies for treatment of neo-epithelial lesions at the SCJ.

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Comparison of newly developed anti-bone morphogenetic protein 4 llama-derived antibodies with commercially available BMP4 inhibitors

Cited by 15 publications

References 59 publications

Bone morphogenetic protein receptor signal transduction in human disease

Bone morphogenetic protein receptor signal transduction in human disease

Enhanced BMP-2/BMP-4 ratio in patients with peripheral spondyloarthritis and in cytokine- and stretch-stimulated mouse chondrocytes

Novel In Vivo Mouse Cryoablation Model to Explore Unique Therapeutic Approaches for Premalignant Columnar Lesions

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