Targeting adipocytic discoidin domain receptor 2 impedes fat gain while increasing bone mass

Yang, Xiaoyu; Li, Jing; Zhao, Laiping; Chen, Yazhuo; Cui, Zhijun; Xu, Taotao; Xu, Li; Wu, Shufang; Zhang, Yan

doi:10.1038/s41418-021-00887-9

Cited by 12 publications

(8 citation statements)

References 49 publications

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“…A limitation of our study is that we used mice with host global DDR2 knockout for our in vivo tumor burden studies. Prior work has shown that DDR2 plays a role in bone development, lipolysis, and ECM deposition in bone and heart [ 51 – 55 ], so it is possible that DDR2’s role in other cell types contributes to the observed tumor burden phenotype. To clarify the specific role of fibroblast DDR2 in tumor progression, we performed the omental colonization assay and determined that CAF DDR2 and arginase affects the early steps of tumor progression.…”

Section: Discussionmentioning

confidence: 99%

DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression

Akinjiyan,

Ibitoye,

Zhao

et al. 2023

Oncogene

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Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, Discoidin Domain Receptor 2 (DDR2), promotes collagen production in human and mouse omental CAFs through arginase activity. CAFs with high DDR2 or arginase promote tumor colonization in the omentum. In addition, DDR2-depleted CAFs had decreased ornithine levels leading to decreased collagen production and polyamine levels compared to WT control CAFs. Tumor cell invasion was decreased in the presence CAF conditioned media (CM) depleted of DDR2 or arginase-1, and this invasion defect was rescued in the presence of CM from DDR2-depleted CAFs that constitutively overexpressed arginase-1. Similarly, the addition of exogenous polyamines to CM from DDR2-depleted CAFs led to increased tumor cell invasion. We detected SNAI1 protein at the promoter region of the arginase-1 gene, and DDR2-depleted CAFs had decreased levels of SNAI1 protein at the arginase-1 promoter region. Furthermore, high stromal arginase-1 expression correlated with poor survival in ovarian cancer patients. These findings highlight how DDR2 regulates collagen production by CAFs in the tumor microenvironment by controlling the transcription of arginase-1, and CAFs are a major source of arginase activity and L-arginine metabolites in ovarian cancer models.

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Section: Discussionmentioning

confidence: 99%

DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression

Akinjiyan,

Ibitoye,

Zhao

et al. 2023

Oncogene

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“…Early studies suggested possible direct effects of DDR2 on these cells such as suppression of insulin stimulated tyrosine phosphorylation of the insulin receptor in the 3T3-L1 adipocyte cell line (112). More recently, direct effects of DDR2 on adipocytes in vivo were examined using Adipo Cre ; Ddr2 fl/fl mice, where Ddr2 is inactivated in peripheral as well as marrow fat (113). In this study, mutant mice were protected from high fat diet-induced weight gain, a response that was attributed to decreased adipocyte size.…”

Section: Metabolic Effects Of Ddr2 Deficiency and Relationship To Bon...mentioning

confidence: 92%

Discoidin domain receptors; an ancient family of collagen receptors has major roles in bone development, regeneration and metabolism

Franceschi

Hallett

2023

Front. Dent. Med

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The extracellular matrix (ECM) niche plays a critical role in determining cellular behavior during bone development including the differentiation and lineage allocation of skeletal progenitor cells to chondrocytes, osteoblasts, or marrow adipocytes. As the major ECM component in mineralized tissues, collagen has instructive as well as structural roles during bone development and is required for bone cell differentiation. Cells sense their extracellular environment using specific cell surface receptors. For many years, specific β1 integrins were considered the main collagen receptors in bone, but, more recently, the important role of a second, more primordial collagen receptor family, the discoidin domain receptors, has become apparent. This review will specifically focus on the roles of discoidin domain receptors in mineralized tissue development as well as related functions in abnormal bone formation, regeneration and metabolism.

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“…Mice lacking DDR2 have reduced body mass index and adipose amount compared to wild type mice ( Kawai et al, 2014 ). Moreover, selective deletion of DDR2 in adipose tissue enhances lipolysis via activation of the Adcy5-cAMP-PKA pathway ( Yang et al, 2022 ). Thus, both DDR1 and DDR2 are positive regulators of fatty metabolism and they could contribute to disease by favoring fatty accumulation and increasing extracellular matrix deposition, thus creating a vicious cycle promoting fibrosis.…”

Section: Discoidin Domain Receptors and Metabolismmentioning

confidence: 99%

Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease

2022

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Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of extracellular matrix (ECM) components leading to fibrosis and organ dysfunction. The synthesis/degradation of ECM components is finely regulated by several factors, including discoidin domain receptors (DDRs). These are receptor tyrosine kinases that are activated by collagens. Upon activation, DDRs control several cell functions that, when exacerbated, contribute to kidney injury and fibrosis. DDRs are undetectable in healthy kidney, but become rapidly upregulated in several kidney fibrotic conditions, thus making them attractive anti-fibrotic targets. DDRs contribute to kidney injury and fibrosis by promoting apoptosis of injured kidney cells, stimulating the production of pro-inflammatory cytokines, and regulating the production of ECM components. They achieve these effects by activating canonical intracellular molecules or by directly interacting with nuclear chromatin and promoting the transcription of pro-fibrotic genes. The goal of this review is to highlight canonical and non-canonical mechanisms whereby DDRs contribute to kidney injury/fibrosis. This review will summarize key findings obtained using cells and mice lacking DDRs and it will discuss the discovery and development of targeted DDR small molecule- and antisense-based inhibitors. Understanding the molecular mechanisms whereby DDRs control kidney injury and fibrosis might enable us to not only develop more selective and potent inhibitors, but to also determine when DDR inhibition needs to be achieved to prevent and/or halt the development of kidney fibrosis.

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Targeting adipocytic discoidin domain receptor 2 impedes fat gain while increasing bone mass

Cited by 12 publications

References 49 publications

DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression

DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression

Discoidin domain receptors; an ancient family of collagen receptors has major roles in bone development, regeneration and metabolism

Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease

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