Functional Characterization of a Small-Molecule Inhibitor of the DKK1-LRP6 Interaction

Iozzi, Sara; Remelli, Rosaria; Lelli, Barbara; Diamanti, Daniela; Pileri, Silvia; Bracci, Luisa; Roncarati, Renza; Caricasole, Andrea; Bernocco, Simonetta

doi:10.5402/2012/823875

Cited by 26 publications

(31 citation statements)

References 40 publications

(37 reference statements)

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“…The small molecule NCI8642/ gallocyanine efficiently displaces DKK1 from LRP6 and blocks DK1 inhibition of canonical Wnt signaling. 32 Interestingly, PAH lung MPCs, but not skin MPCs, expressed increased levels of the DKK1 inhibitor RSPO2. RSPO2, or r-spondin 2, also activates canonical Wnt signaling by inhibiting the DKK1-LRP6 interaction.…”

Section: Discussionmentioning

confidence: 99%

“…via stimulation of receptor internalization, 26,32,49,50 which is regulated by CAV1, a mutation associated with HPAH. 51,52 Interestingly, DKK activity is also regulated by hormone levels, including aldosterone, estrogen, and parathyroid hormone, which is particularly important, given that PAH affects predominantly females.…”

Section: Discussionmentioning

confidence: 99%

“…63 Increased DKK1 and LRP6 activity has been associated with the development and poor prognosis of cancers. 32,64 Both molecules are currently under study as therapeutic targets. Current systemic inhibition of Wnt signaling has negative side effects, highlighting the need for the identification and development of novel targets and inhibitors as well as an understanding of the cell-specific variations in DKK1-LRP6-regulated Wnt signaling, as a result of decreased BMPR2 signaling, even within the pulmonary vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…26,32,41,49 DKK1 binding to LRP6 may also decrease Wnt/β-catenin signaling map analysis of gene similarities and segregation between control skin and lung MPCs; yellow and red indicate high and low levels of expression, respectively. M-O, Probes belonging to gene ontology functional categories were selected from the whole expression data of the lung and skin MPC groups, and corresponding heat maps of expression data were constructed.…”

Section: Discussionmentioning

confidence: 99%

“…To test the effect of the converse, we treated the control or BMPR2-mutant PAH MPCs with a DKK1 antagonist, gallocyanine, 32 and decreased the expression of all the genes, with the exception of LRP6. Taken together these results suggest that decreased BMPR2 signaling inherently alters the PAH MPCs, driving an abnormal response to DKK1, and that this pathway is targetable.…”

Section: Targeting Of the Dkk1-lrp6 Axis In Bmpr2-mutant Pah Mpcsmentioning

confidence: 99%

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Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

et al. 2016

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Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that actively participates in disease processes, as well as the potential to translate these findings to vascular beds in other nonlung tissues, in this instance perivascular skin mesenchymal cells (MCs). We utilized posttransplant or autopsy lung explant-derived cells (ABCG2-expressing mesenchymal progenitor cells [MPCs], fibroblasts) and skin-derived MCs to test the hypothesis that perivascular ABCG2 MPCs derived from pulmonary arterial hypertension (PAH) patient lung and skin would express a gene profile reflective of ongoing vascular dysfunction. By analyzing the genetic signatures and pathways associated with abnormal ABCG2 lung MPC phenotypes during PAH and evaluating them in lung-and skinderived MCs, we have identified potential predictor genes for detection of PAH as well as a targetable mechanism to restore MPCs and microvascular function. These studies are the first to explore the utility of expanding the study of ABCG2 MPC regulation of the pulmonary microvasculature to the epidermis, in order to identify potential markers for adult lung vascular disease, such as PAH.Keywords: mesenchymal progenitor cells, skin, lung, microvascular, pulmonary hypertension, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, BMPR2, Wnt signaling, LRP6, DKK1. Pulmonary vascular dysfunction or disease (PVD) is characterized by altered lung vascular structure and function. A significant loss of vascular-bed function, as seen in PVD, is thought to precede the clinical presentation of pulmonary hypertension (PH). 1 PH is associated with a wide array of comorbid conditions, such as systemic sclerosis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, and also occurs as a primary PVD known as either idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH). 2-4 PH is characterized by elevated pulmonary artery pressures and widespread vascular remodeling, including endothelial cell dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. 5-7 All forms of PH have a high mortality rate despite current therapeutic options. The current limited understanding of PVD as a predecessor to PH and lack of diagnostic approaches or criteria specific to preclinical PVD have hampered the study of the early stages of PVD in both rodent models and the clinical setting.Approximately 80% of HPAH patients have a known mutation in the gene bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation-associated PAH is an autosomal dominant disease with low penetrance (approx. 20%); hence, not all mutation carriers develop PAH. In addition, approximately 20% of patients initially labeled as having IPAH also have a mutation in BMPR2 and thus heritable disease. 8 In addition to ge...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Targeting Of the Dkk1-lrp6 Axis In Bmpr2-mutant Pah Mpcsmentioning

confidence: 99%

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Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

et al. 2016

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Experimental Methods Used for Identifying Small-Molecule Inhibitors of Protein-Protein Interaction

Zhou

Kong

et al. 2018

Targeting Protein-Protein Interactions by Small Molecules

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Serum concentration of dickkopf-related protein 1 (DKK1) in psoriatic arthritis in the context of bone remodelling

Biedroń,

Czepiel,

Siedlar

et al. 2023

Rheumatol Int

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Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by the pathological occurrence of two opposite phenomena—osteoresorption and osteogenesis. Dickkopf-related protein 1 (DKK1) which inhibits the Wingless protein (Wnt) signalling pathway has been shown to be a master regulator of bone remodeling in inflammatory rheumatic diseases. However, the exact relationship between DKK1 serum level and bone remodelling is not clear. The goal of this study is to review state-of-the-art knowledge on the association of serum DKK1 with a bone remodelling in PsA. The MEDLINE-PubMed, EMBASE, Scopus, Web of Science and DOAJ databases were searched for appropriate papers. The English terms: ‘DKK1’, ‘Dickkopf-1’ ‘Dickkopf related protein 1’, ‘psoriatic arthritis’ and ‘PsA’ were used for search purposes. Eight original articles and two reviews were identified up to August 2023. In four out of 8 discussed studies DKK1 serum level was higher in PsA patients than in healthy controls [Dalbeth, p < 0.01; Diani, p < 0.001; Chung, p < 0.01; Abd el Hamid, p < 0.001)], it was comparable in another (Daousiss, p = 0.430) and was lower in two (Fassio2017, p < 0.05; Fassio2019, p < 0.05). In one study, the comparative groups included patients with axial spondyloarthritis, where DKK1 serum levels were lower in PsA groups [Jadon, peripheral PsA, p = 0.01]. The true relative serum concentration of DKK1 in PsA, as well as its influence on osteogenesis and osteoresorption, is still equivocal. Further studies on this matter with consistent and stringent methodology are warranted.

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Functional Characterization of a Small-Molecule Inhibitor of the DKK1-LRP6 Interaction

Cited by 26 publications

References 40 publications

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

Experimental Methods Used for Identifying Small-Molecule Inhibitors of Protein-Protein Interaction

Serum concentration of dickkopf-related protein 1 (DKK1) in psoriatic arthritis in the context of bone remodelling

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