ATF3 deficiency in chondrocytes alleviates osteoarthritis development

Iezaki, Takashi; Ozaki, Kakeru; Fukasawa, Kazuya; Inoue, Makoto; Kitajima, Shigetaka; Muneta, Takeshi; Takeda, Satoshi; Fujita, Hiroyuki; Onishi, Yuki; Horie, Tetsuhiro; Yoneda, Yukio; Takarada, Takeshi; Hinoi, Eiichi

doi:10.1002/path.4739

Cited by 45 publications

(38 citation statements)

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“…chondrocytes (48) and that the NF-kB signaling pathway triggers production of catabolic and inflammatory biomarkers in chondrocytes (49). In the current study, the results suggest that ghrelin activated Akt signaling and promoted anabolism of chondrocytes while suppressing the expression of catabolic and inflammatory biomarkers.…”

Section: Ghrelin Antagonizes Exaggerated Catabolism In Degenerative Csupporting

confidence: 55%

“…Disorganization of metabolism in OA involves impaired anabolism and abnormally enhanced catabolism, and activation of NF‐κB signaling is known to play a predominant role in cartilage degradation of OA (47). It is reported that NF‐κB signaling represses anabolism of chondrocytes (48) and that the NF‐κB signaling pathway triggers production of catabolic and inflammatory biomarkers in chondrocytes (49). In the current study, the results suggest that ghrelin activated Akt signaling and promoted anabolism of chondrocytes while suppressing the expression of catabolic and inflammatory biomarkers.…”

Section: Resultsmentioning

confidence: 99%

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Ghrelin protects against osteoarthritis through interplay with Akt and NF‐κB signaling pathways

Chen

Wang

et al. 2018

FASEB j.

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Osteoarthritis (OA) is a common chronic degenerative disease characterized by degeneration in the joints and subsequent destruction of cartilage and bone, yet much remains to be elucidated regarding its molecular mechanism. Ghrelin is a recently discovered neuropeptide with anti-inflammatory actions, but it is unknown whether ghrelin is involved in OA. Human primary chondrocyte and cartilage samples were collected from patients with OA, and the expression pattern of ghrelin was assessed. Human chondrocyte and cartilage samples were stimulated with IL-1β and TNF-α, and exogenous ghrelin-alleviated disorganization of catabolism and anabolism were mediated by IL-1β and TNF-α. Destabilization of the medial meniscus and anterior cruciate ligament transection models were established in wild-type mice that were administered ghrelin or PBS. Severity of inflammation and degeneration in the joints were determined by measuring the levels of various inflammatory cytokines and degeneration-associated molecules. Ghrelin down-regulated the production of various inflammatory cytokines, inhibited apoptosis of chondrocytes, decreased the levels of metalloproteinases (including matrix metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motif-5), and maintained the expression of critical matrix components, such as aggrecan and collagen 2. Moreover, suppression of the Akt signaling pathway and activation of NF-κB signaling in chondrocytes during OA development was antagonized by ghrelin administration. This supports the assessment of ghrelin as a potential therapeutic approach to treat degenerative cartilage diseases, including OA.-Qu, R., Chen, X., Wang, W., Qiu, C., Ban, M., Guo, L., Vasilev, K., Chen, J., Li, W., Zhao, Y. Ghrelin protects against osteoarthritis through interplay with Akt and NF-κB signaling pathways.

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Section: Ghrelin Antagonizes Exaggerated Catabolism In Degenerative Csupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Ghrelin protects against osteoarthritis through interplay with Akt and NF‐κB signaling pathways

Chen

Wang

et al. 2018

FASEB j.

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“…Embryos were then immersed in Alcian blue solution overnight, and were transferred in a solution of 2% KOH, followed by staining in alizarin red solution overnight. Finally, the skeletons were cleaned with 1% KOH/20% glycerol and then stored in 50% ethanol/50% glycerol (Iezaki et al., 2016). …”

Section: Methodsmentioning

confidence: 99%

Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

et al. 2018

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SummaryThe mechanistic/mammalian target of rapamycin complex 1 (mTORC1) regulates cellular function in various cell types. Although the role of mTORC1 in skeletogenesis has been investigated previously, here we show a critical role of mTORC1/4E-BPs/SOX9 axis in regulating skeletogenesis through its expression in undifferentiated mesenchymal cells. Inactivation of Raptor, a component of mTORC1, in limb buds before mesenchymal condensations resulted in a marked loss of both cartilage and bone. Mechanistically, we demonstrated that mTORC1 selectively controls the RNA translation of Sox9, which harbors a 5′ terminal oligopyrimidine tract motif, via inhibition of the 4E-BPs. Indeed, introduction of Sox9 or a knockdown of 4E-BP1/2 in undifferentiated mesenchymal cells markedly rescued the deficiency of the condensation observed in Raptor-deficient mice. Furthermore, introduction of the Sox9 transgene rescued phenotypes of deficient skeletal growth in Raptor-deficient mice. These findings highlight a critical role of mTORC1 in mammalian skeletogenesis, at least in part, through translational control of Sox9 RNA.

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“…First shown to promote collagen synthesis and cell type-specific genes in OBs, it was subsequently found to stimulate CC proliferation and PHC differentiation, namely through upregulating Ihh expression [147]. Although earlier studies suggested that ATF3 could participate in promoting HC differentiation, conditional inactivation in chondrocytes ( Col2Cre ), revealed that ATF3 is dispensable for cartilage development [148]. The factor, however, exacerbates post-traumatic osteoarthritis downstream of inflammatory cytokines.…”

Section: Basic-domain Transcription Factorsmentioning

confidence: 99%

Transcriptional control of chondrocyte specification and differentiation

Liu

Samsa

Zhou

et al. 2017

Seminars in Cell & Developmental Biology

145

112

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A milestone in the evolutionary emergence of vertebrates was the invention of cartilage, a tissue that has key roles in modeling, protecting and complementing the bony skeleton. Cartilage is elaborated and maintained by chondrocytes. These cells derive from multipotent skeletal progenitors and they perform highly specialized functions as they proceed through sequential lineage commitment and differentiation steps. They form cartilage primordia, the primary skeleton of the embryo. They then transform these primordia either into cartilage growth plates, temporary drivers of skeletal elongation and endochondral ossification, or into permanent tissues, namely articular cartilage. Chondrocyte fate decisions and differentiated activities are controlled by numerous extrinsic and intrinsic cues, and they are implemented at the gene expression level by transcription factors. The latter are the focus of this review. Meritorious efforts from many research groups have led over the last two decades to the identification of dozens of key chondrogenic transcription factors. These regulators belong to all types of transcription factor families. Some have master roles at one or several differentiation steps. They include SOX9 and RUNX2/3. Others decisively assist or antagonize the activities of these masters. They include TWIST1, SOX5/6, and MEF2C/D. Many more have tissue-patterning roles and regulate cell survival, proliferation and the pace of cell differentiation. They include, but are not limited to, homeodomain-containing proteins and growth factor signaling mediators. We here review current knowledge of all these factors, one superclass, class, and family at a time. We then compile all knowledge into transcriptional networks. We also identify remaining gaps in knowledge and directions for future research to fill these gaps and thereby provide novel insights into cartilage disease mechanisms and treatment options.

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ATF3 deficiency in chondrocytes alleviates osteoarthritis development

Cited by 45 publications

References 45 publications

Ghrelin protects against osteoarthritis through interplay with Akt and NF‐κB signaling pathways

Ghrelin protects against osteoarthritis through interplay with Akt and NF‐κB signaling pathways

Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

Transcriptional control of chondrocyte specification and differentiation

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