BMP-7 Modulates Hyaluronan-Mediated Proximal Tubular Cell-Monocyte Interaction

Selbi, Wisam Dhafir Rashid; Motte, Carol D. De La; Hascall, Vincent C.; Phillips, Aled O.

doi:10.1097/01.asn.0000125619.27422.8e

Cited by 51 publications

(57 citation statements)

References 48 publications

(41 reference statements)

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“…Many cell types assemble HA in an organized pericellular coat in vitro, in which the HA is anchored to the cell surface by CD44 (16,(31)(32)(33)(34)(35). Our recent studies in proximal tubular epithelial cells have investigated the roles of the I␣I family of hyaladherin proteins, together with TSG-6 and the HA-binding proteoglycans bikunin and versican, in the macromolecular assembly of HA by PTC (16,25,35,36). The results demonstrated that the TSG-6-mediated formation of I␣I HC⅐HA complexes was critical for the formation of a pericellular HA matrix.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Martin

Midgley

Meran

et al. 2016

Journal of Biological Chemistry

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Fibroblasts are central to wound healing and fibrosis through TGF␤1-triggered differentiation into contractile, ␣-smooth muscle actin (␣-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-␣-inhibitor (I␣I) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and ␣-SMA had different kinetics of induction by TGF␤1, with TSG-6 peaking before ␣-SMA. Si CD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing I␣I heavy chain (HC) transfer), HA-oligosaccharides, cobalt, or Si bikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG-6/I␣I HC interaction was necessary for the effect of TSG-6 and that HC stabilization of HA initiated the CD44/EGFR association. The newly described HC5 was shown to be the principal HC expressed, and its cell surface expression was prevented by siRNA inhibition of TSG-6 or bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knockdown by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGF␤1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target.The fibroblast is the most abundant cell type in normal connective tissues. It plays a central role in the synthesis, degradation, and remodeling of extracellular matrix both in health and in disease. At sites of tissue damage and in the context of wound healing, activated fibroblasts, termed myofibroblasts, with a contractile phenotype, characterized by the expression of the smooth muscle isoform of ␣-actin (␣-SMA), 3 are essential for the synthesis of a collagen-rich scar, providing the force for wound contraction (1). During a healing response, myofibroblasts are a transient cell population (2). Myofibroblasts are also the major effectors of fibrosis; their persistent presence has been established as the best marker of numerous types of progressive organ dysfunction, such as that seen in chronic renal failure of various etiologies (3-7), liver disease (8), and pulmonary fibrosis (9).The cytokine TGF␤1 is a well recognized mediator of progressive tissue fibrosis, and in vitro and in vivo evidence suggests that it is the primary driving force in fibroblast-myofibroblast phenotypic activation (10, 11). The sequence of events leading up to this transformation is being increasingly characterized at a molecular level in an attempt to understan...

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Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Martin

Midgley

Meran

et al. 2016

Journal of Biological Chemistry

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“…BMP7 signaling limits excessive tissue injury by suppressing initiation of the inflammatory response by tubular epithelial cells. 4,[11][12][13] Immune surveillance is required for maintenance of the healthy kidney, and antagonism of BMP7 may therefore be necessary for tissue homeostasis. Upon ischemic injury, release of antagonism by degeneration of the CHRDL1-expressing S3 segment would facilitate BMP7 signaling required to counteract the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…11 In addition, BMP7 changes the conformation of cell-surface hyaluronic acid on proximal tubule cells, altering monocyte binding and preventing increased TGF-␤ production. 12,13 BMPs signal by binding serine-threonine kinase receptors, which phosphorylate Smad transcription factors. Association of Smads with cell type-specific transcription factors determines transcriptional outcomes, enabling context-dependent responses.…”

mentioning

confidence: 99%

Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

Larman

Karolak²,

Adams³

et al. 2009

Journal of the American Society of Nephrology

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Stimulation of the bone morphogenetic protein (BMP) pathway protects the kidney from acute and chronic injury. Numerous regulators in the kidney control BMP signaling, offering many targets for therapeutic manipulation. Here, we screened for modulators of BMP signaling in the ischemia-sensitive S3 segment and found that Chordin-like 1 is expressed in this segment of both the mouse and human nephron. Chordin-like 1 specifically antagonizes BMP7, which is expressed in the neighboring distal nephron, and this depends on the presence of the protein Twisted gastrulation. Upon ischemia-induced degeneration of the S3 segment, we observed a reduction in Chordin-like 1 expression coincident with intense BMP signaling in tubules of the recovering kidney. Restored expression accompanied proximal tubule epithelia redifferentiation, again coincident with decreased BMP signaling. We propose that Chordin-like 1 reduces BMP7 signaling in healthy proximal tubules, and the loss of this activity upon sloughing of injured epithelia promotes BMP7 signaling in repopulating, dedifferentiated epithelia. As regenerating epithelia differentiate, Chordin-like 1 is again expressed, antagonizing BMP7. These data suggest a mechanism for dynamic regulation of renoprotective BMP7 signaling in the S3 segment of the proximal tubule.

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“…We also recently identified a novel mechanism by which monocytes interact with PTC and is dependent on CD44-mediated adhesion of monocytes to hyaluronan (HA)-based structures generated on the PTC cell surface (9). We also demonstrated that bone morphogenic protein-7 (BMP-7) stimulates the formation of HA cables and also increases HA-dependent monocyte interaction with PTC.…”

mentioning

confidence: 93%

Bone Morphogenic Protein-7 Inhibits Monocyte-Stimulated TGF-β1 Generation in Renal Proximal Tubular Epithelial Cells

Zhang¹,

Selbi²,

Motte³

et al. 2005

Journal of the American Society of Nephrology

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BMP-7 Modulates Hyaluronan-Mediated Proximal Tubular Cell-Monocyte Interaction

Cited by 51 publications

References 48 publications

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

Bone Morphogenic Protein-7 Inhibits Monocyte-Stimulated TGF-β1 Generation in Renal Proximal Tubular Epithelial Cells

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