YAP/TAZ regulates the expression of proteoglycan 4 and tenascin C in superficial-zone chondrocytes

Delve, E.; Co, Vivian; Regmi, Suresh C.; Parreno, Justin; Schmidt, Tannin A.; Kandel, Rita A.

doi:10.22203/ecm.v039a03

Cited by 19 publications

(22 citation statements)

References 35 publications

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“…Among the few cell types tolerant to neoplastic EWS-FLI1 transformation in the mouse are osteochondrogenic progenitors of the embryonal bone superficial zone [170]. In these cells, YAP and TAZ regulate the expression of secreted ECM proteins proteoglycan 4 (PRG4) and tenascin C (TNC) downstream of CDC42 signaling [200].…”

Section: Yap/taz In Ewing Sarcomamentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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Section: Yap/taz In Ewing Sarcomamentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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“…Yap knockout exerted maintaining the expression of type II collagen and inhibiting cartilage degeneration in the OA model (Ying et al 2018 ). In addition, intra-articular injection of YAP-siRNA or verteporfin, a selective inhibitor of YAP, significantly reduced abnormal subchondral bone formation, and preserved cartilage homeostasis in mice OA model (Delve et al 2020 ). On the contrary, some scholars think that overexpression of YAP is helpful to preserve the integrity of articular cartilage, and the absence of YAP leads to the destruction of cartilage.…”

Section: Discussionmentioning

confidence: 99%

G protein coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocyte in osteoarthritis via suppression of Piezo1

Sun

Leng

Guo

et al. 2021

Mol Med

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Background Apoptosis of chondrocyte is involved in osteoarthritis (OA) pathogenesis, and mechanical stress plays a key role in this process by activation of Piezo1. However, the negative regulation of signal conduction mediated by mechanical stress is still unclear. Here, we elucidate that the critical role of G protein coupled estrogen receptor (GPER) in the regulation of mechanical stress-mediated signal transduction and chondrocyte apoptosis. Methods The gene expression profile was detected by gene chip upon silencing Piezo1. The expression of GPER in cartilage tissue taken from the clinical patients was detected by RT-PCR and Western blot as well as immunohistochemistry, and the correlation between GPER expression and OA was also investigated. The chondrocytes exposed to mechanical stress were treated with estrogen, G-1, G15, GPER-siRNA and YAP (Yes-associated protein)-siRNA. The cell viability of chondrocytes was measured. The expression of polymerized actin and Piezo1 as well as the subcellular localization of YAP was observed under laser confocal microscope. Western blot confirmed the changes of YAP/ Rho GTPase activating protein 29 (ARHGAP29) /RhoA/LIMK /Cofilin pathway. The knee specimens of osteoarthritis model were stained with safranin and green. OARSI score was used to evaluate the joint lesions. The expressions of GPER and YAP were detected by immunochemistry. Results Expression profiles of Piezo1- silenced chondrocytes showed that GPER expression was significantly upregulated. Moreover, GPER was negatively correlated with cartilage degeneration during OA pathogenesis. In addition, we uncovered that GPER directly targeted YAP and broadly restrained mechanical stress-triggered actin polymerization. Mechanism studies revealed that GPER inhibited mechanical stress-mediated RhoA/LIMK/cofilin pathway, as well as the actin polymerization, by promoting expression of YAP and ARHGAP29, and the YAP nuclear localization, eventually causing the inhibition of Piezo1. YAP was obviously decreased in degenerated cartilage. Silencing YAP caused significantly increased actin polymerization and activation of Piezo1, and an increase of chondrocyte apoptosis. In addition, intra-articular injection of G-1 to OA rat effectively attenuated cartilage degeneration. Conclusion We propose a novel regulatory mechanism underlying mechanical stress-mediated apoptosis of chondrocyte and elucidate the potential application value of GPER as therapy targets for OA.

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“…Understanding its transcriptional regulation may be key to preventing disease progression. Previous work has provided evidence of prg4 regulation via TGFβ (Chavez et al, 2019), Creb5 (Zhang et al, 2021), Yap/Taz (Delve et al, 2020) and load-induced Cox2 (Abusara et al, 2013; Ogawa et al, 2014). In our present study, the decreased response to Ihh signaling detected in the non-mineralized chondrocytes of immature mutant AC was accompanied by reductions of Prg4 .…”

Section: Discussionmentioning

confidence: 99%

Primary cilia drive postnatal tidemark patterning in articular cartilage by coordinating responses to Indian Hedgehog and mechanical load

Rux

Helbig

Han

et al. 2021

Preprint

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Articular cartilage (AC) is essential for body movement, but is highly susceptible to degenerative diseases and has poor self-repair capacity. To improve current subpar regenerative treatment, developmental mechanisms of AC should be clarified and, specifically, how postnatal multi-zone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis and while the importance of chondrocyte primary cilia is well appreciated their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss-of-function approach (Ift88-flox) targeting joint-lineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected, however mature AC (aged 2 months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30-50%. In addition, we discovered the surprising findings that tidemark patterning was severely disrupted and accompanied alterations in hedgehog signaling that were also dependent on regional load-bearing functions of AC. Interestingly, Prg4 expression was also increased in those loaded sites. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis, dictating tidemark topography, zonal matrix composition and mechanical load responses.

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YAP/TAZ regulates the expression of proteoglycan 4 and tenascin C in superficial-zone chondrocytes

Cited by 19 publications

References 35 publications

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

G protein coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocyte in osteoarthritis via suppression of Piezo1

Primary cilia drive postnatal tidemark patterning in articular cartilage by coordinating responses to Indian Hedgehog and mechanical load

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