A Stem Cell–Based Approach to Cartilage Repair

Johnson, Kristen; Zhu, Shoutian; Tremblay, Matthew S.; Payette, Joshua N.; Wang, Jianbo; Bouchez, Laure C.; Meeusen, Shelly; Althage, Alana; Cho, Charles Y.; Wu, Xu; Schultz, Peter G.

doi:10.1126/science.1215157

Cited by 619 publications

(643 citation statements)

References 36 publications

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“…Nuclear and cytosolic content fractionation was performed following the protocol reported in previous studies (31,41). Fractions were subjected to SDS/PAGE electrophoresis and Western blotting using primary antibodies recognizing target proteins, including NME2 (Abcam), MYC (Cell Signaling), ERK1/2 (Cell Signaling), α-and γ-tubulin (Sigma), and fluorophore-conjugated secondary antibodies (LI-COR) and scanned using an Odyssey CLx imager.…”

Section: Methodsmentioning

confidence: 99%

Small molecule selectively suppresses MYC transcription in cancer cells

Bouvard

Lim

Ludka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in downregulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYCdependent tumors.MYC | stauprimide | NME2 | nuclear localization | cancer T he transcription factor MYC participates in diverse cellular processes by regulating the transcription of a large number of genes involved in gene expression, cell division, apoptosis, cell adhesion, stem cell self-renewal and differentiation, and metabolism (1-3). MYC is an oncogene whose expression is elevated in up to 75% of all cancers with various tissue origins (4); MYC expression levels also correlate with prognostic outcomes in patients of various types of malignancies (5, 6). In addition to its well-established roles in tumor initiation and cancer cell survival and proliferation, MYC has been shown to be involved in tumor microenvironment remodeling, drug resistance, and cancer stem cell maintenance (7-9). Recent studies have also revealed a role for MYC in regulating the transcription of immune checkpoint genes, including CD47 and PD-L1 in cancer cells, suggesting that MYC is involved in cancer escape from immune surveillance (10).Overexpression of MYC is able to induce malignant transformation in skin (11), lung (12), liver (13), breast (14, 15), and hematopoietic cells (16) in transgenic mouse models, and termination of MYC overexpression results in halted cancer cell proliferation, increased apoptosis and terminal differentiation, and tumor regression. Furthermore, inhibition of endogenous MYC by the inducible expression of a dominant-negative variant of MYC, Omomyc, is able to induce tumor regression in transgenic mouse models of lung cancer (17). More intriguingly, transient deactivation of MYC overexpression (18) and episodic expression of Omomyc (19) have been shown to induce irreversible tumor regression in osteosarcoma and lung cancer transgenic mouse models, suggesting the potential of MYCtargeted anticancer therapies.Drug discovery efforts have attempted to directly and indirectly modulate MYC-dependent transcription. For example, compounds have been identified that disrupt the interaction between MYC and its transcriptional partner MAX to suppress downstream gene transcription (20)(21)(22)(23)(2...

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Section: Methodsmentioning

confidence: 99%

Small molecule selectively suppresses MYC transcription in cancer cells

Bouvard

Lim

Ludka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, agents capable of inhibiting the formation of MFBs in the presence of TGF-β1 without directly inhibiting TGF-β1 signaling itself, may have an advantage over direct suppression of TGF-β1, which has the potential to exacerbate immune responses. Cell-based phenotypic screens have proven an effective strategy to identify molecules that affect cell fate by previously unknown mechanisms (4,5). Herein we undertook an image-based screen of MFB transdifferentiation that led to the discovery of an antifibrotic agent with excellent preclinical in vivo activity and that acts by a unique mechanism of action.…”

mentioning

confidence: 99%

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Bollong

Yang

Vergani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fibrosis, a disease in which excessive amounts of connective tissue accumulate in response to physical damage and/or inflammatory insult, affects nearly every tissue in the body and can progress to a state of organ malfunction and death. A hallmark of fibrotic disease is the excessive accumulation of extracellular matrix-secreting activated myofibroblasts (MFBs) in place of functional parenchymal cells. As such, the identification of agents that selectively inhibit the transdifferentiation process leading to the formation of MFBs represents an attractive approach for the treatment of diverse fibrosis-related diseases. Herein we report the development of a high throughput image-based screen using primary hepatic stellate cells that identified the antifungal drug itraconazole (ITA) as an inhibitor of MFB cell fate in resident fibroblasts derived from multiple murine and human tissues (i.e., lung, liver, heart, and skin). Chemical optimization of ITA led to a molecule (CBR-096-4) devoid of antifungal and human cytochrome P450 inhibitory activity with excellent pharmacokinetics, safety, and efficacy in rodent models of lung, liver, and skin fibrosis. These findings may serve to provide a strategy for the safe and effective treatment of a broad range of fibrosis-related diseases.

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“…Exciting new approaches, such as the use of poly‐micelle protected Runx1 mRNA,95 demonstrates that, in principle, articular cartilage is amenable to RNA‐based therapeutics. Given that small molecules with Runx1 ‐mediated chondroprotective properties, including kartogenin 96 and TD‐198946,97, 98 have been defined using high‐throughput candidate molecule screens and not systems biology approaches, can systems orientated approaches solve the problem of defining novel therapeutic targets? Systems orientated approaches augment, but do not replace reductionist strategies.…”

Section: Biology As a Systemmentioning

confidence: 99%

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

Mueller

Peffers

Proctor³

et al. 2017

J. Orthop. Res.

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Systems orientated research offers the possibility of identifying novel therapeutic targets and relevant diagnostic markers for complex diseases such as osteoarthritis. This review demonstrates that the osteoarthritis research community has been slow to incorporate systems orientated approaches into research studies, although a number of key studies reveal novel insights into the regulatory mechanisms that contribute both to joint tissue homeostasis and its dysfunction. The review introduces both top‐down and bottom‐up approaches employed in the study of osteoarthritis. A holistic and multiscale approach, where clinical measurements may predict dysregulation and progression of joint degeneration, should be a key objective in future research. The review concludes with suggestions for further research and emerging trends not least of which is the coupled development of diagnostic tests and therapeutics as part of a concerted effort by the osteoarthritis research community to meet clinical needs. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1573–1588, 2017.

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A Stem Cell–Based Approach to Cartilage Repair

Cited by 619 publications

References 36 publications

Small molecule selectively suppresses MYC transcription in cancer cells

Small molecule selectively suppresses MYC transcription in cancer cells

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

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