Time has come to address the spatiotemporal combinatorial model for CCN proteins biological activitites by spatial transcriptomics and genome wide association studies

Perbal, Bernard

doi:10.1007/s12079-023-00729-y

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…CCN2 is known to have autocrine feedback loops on itself and its binding partners [ 25 , 66 , 67 ], so that inhibition of its function results in a decrease in the expression of CCN2, but also in the many partners with whom it interacts. The changes in phosphorylated β-catenin and CCN3 observed in this study may be the result of downregulation of CCN2 after the anti-CCN2 (FG-3019) treatment [ 34 ] (discussed further below), or unknown physical interactions between CCN2 and 3 that mediate their antagonistic effects [ 49 , 68 , 69 ].The anti-CCN2 (FG-3019) could also act as a clearance antibody, removing CCN2 from the vicinity of the cells or interfering in its interactions with some of its putative binding partners [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury

Lambi,

DeSante,

Patel

et al. 2023

IJMS

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The matricellular protein cell communication factor 2/connective tissue growth factor (CCN2/CTGF) is critical to development of neuromuscular fibrosis. Here, we tested whether anti-CCN2 antibody treatment will reduce established forepaw fibro-degenerative changes and improve function in a rat model of overuse injury. Adult female rats performed a high repetition high force (HRHF) task for 18 weeks. Tissues were collected from one subset after 18 wks (HRHF-Untreated). Two subsets were provided 6 wks of rest with concurrent treatment with anti-CCN2 (HRHF-Rest/anti-CCN2) or IgG (HRHF-Rest/IgG). Results were compared to IgG-treated Controls. Forepaw muscle fibrosis, neural fibrosis and entheseal damage were increased in HRHF-Untreated rats, compared to Controls, and changes were ameliorated in HRHF-Rest/anti-CCN2 rats. Anti-CCN2 treatment also reduced phosphorylated-β-catenin (pro-fibrotic protein) in muscles and distal bone/entheses complex, and increased CCN3 (anti-fibrotic) in the same tissues, compared to HRHF-Untreated rats. Grip strength declines and mechanical sensitivity observed in HRHF-Untreated improved with rest; grip strength improved further in HRHF-Rest/anti-CCN2. Grip strength declines correlated with muscle fibrosis, entheseal damage, extraneural fibrosis, and decreased nerve conduction velocity, while enhanced mechanical sensitivity (a pain-related behavior) correlated with extraneural fibrosis. These studies demonstrate that blocking CCN2 signaling reduces established forepaw neuromuscular fibrosis and entheseal damage, which improves forepaw function, following overuse injury.

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Section: Discussionmentioning

confidence: 99%

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury

Lambi,

DeSante,

Patel

et al. 2023

IJMS

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“…As we have already advocated (Perbal 2023), the advent of spatial biology combined to Wide Genome Association studies, has proved very helpful along deciphering the genetics of cancer. Invoking similar approaches would be very helpful to decipher the interplay of multiple biological signaling pathways and determine more precisely the place of the CCN proteins in this system.…”

Section: From Reductionism To Interactions Network: the Third Interac...mentioning

confidence: 99%

Cooperation is the key: the CCN biological system as a gate to high complex protein superfamilies’ signaling

Perbal¹,

Perbal

Perbal³

2023

J. Cell Commun. Signal.

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Cellular signaling is generally understood as the support of communication between contiguous cells belonging to the same tissue or cells being far apart of each other, at a molecular scale, when the message emitted by the transmitters is traveling in liquid or solid matter to reach recipient targets. Subcellular signaling is also important to ensure the proper cell constitution and functioning. However cell signaling is mostly used in the first understanding, to describe how the message sent from one point to another one, will reach a target where it will be interpreted. The Cellular Communication Network (CCN) factors (Perbal et al. 2018) constitute a family of biological regulators thought to be responsible for signaling pathways coordination (Perbal 2018). Indeed, these proteins interact with a diverse group of cell receptors, such as integrins, low density lipoprotein receptors, heparan sulfate proteoglycan receptors (HSPG), and the immunoglobulin superfamily expressed exclusively in the nervous system, or with soluble factors such as bone morphogenetic proteins (BMPS) and other growth factors such as vascular endothelial growth factor, fibroblastic growth factor, and transforming growth factor (TGFbeta). Starting from the recapitulation of basic concepts in enzymology and protein-ligands interactions, we consider, in this manuscript, interpretations of the mechanistic interactions that have been put forward to explain the diversity of CCN proteins biological activities. We suggest that the cross-talks between superfamilies of proteins under the control of CCNs might play a central role in the coordination of developmental signaling pathways KeywordsCellular communication network (CCN) factors • CCN proteins • Protein-ligands interactions • Enzymology • Signaling coordination • Signaling pathways • Regulatory factors cooperation • Proteome • String predictions • Proteinprotein interactions • Phylogenetics • Evolution • Combinations • Spatiotemporal regulation • Combinatorial events • Cellular targets • Reductionnism "Either the activities of each [CCN]module add up or they confer on the whole protein specific functions that might substitute or add to the function of the individual modules" Perbal (2001).

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CCN proteins: opportunities for clinical studies—a personal perspective

Yeger

2023

J. Cell Commun. Signal.

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The diverse members of the CCN family now designated as CCN1(CYR61), CCN2 (CTGF), CCN3(NOV), CCN4(WISP1), CCN5(WISP2), CCN6(WISP3) are a conserved matricellular family of proteins exhibiting a spectrum of functional properties throughout all organs in the body. Interaction with cell membrane receptors such as integrins trigger intracellular signaling pathways. Proteolytically cleaved fragments (constituting the active domains) can be transported to the nucleus and perform transcriptional relevant functional activities. Notably, as also found in other protein families some members act opposite to others creating a system of functionally relevant checks and balances. It has become apparent that these proteins are secreted into the circulation, are quantifiable, and can serve as disease biomarkers. How they might also serve as homeostatic regulators is just becoming appreciated. In this review I have attempted to highlight the most recent evidence under the subcategories of cancer and non‐cancer relevant that could lead to potential therapeutic approaches or ideas that can be factored into clinical advances. I have added my own personal perspective on feasibility.

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Time has come to address the spatiotemporal combinatorial model for CCN proteins biological activitites by spatial transcriptomics and genome wide association studies

Cited by 3 publications

References 17 publications

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury

Cooperation is the key: the CCN biological system as a gate to high complex protein superfamilies’ signaling

CCN proteins: opportunities for clinical studies—a personal perspective

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