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Review
. 2014 Dec;358(3):633-49.
doi: 10.1007/s00441-014-2010-x. Epub 2014 Oct 14.

A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration

Ying Zhang  1 , Tyler Pizzute, Ming Pei
Affiliations
Review

A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration

Ying Zhang et al. Cell Tissue Res. 2014 Dec.

Abstract

Chondrogenesis is a developmental process that is controlled and coordinated by many growth and differentiation factors, in addition to environmental factors that initiate or suppress cellular signaling pathways and the transcription of specific genes in a temporal-spatial manner. As key signaling molecules in regulating cell proliferation, homeostasis and development, both mitogen-activated protein kinases (MAPK) and the Wnt family participate in morphogenesis and tissue patterning, playing important roles in skeletal development, especially chondrogenesis. Recent findings suggest that both signals are also actively involved in arthritis and related diseases. Despite the implication that crosstalk between MAPK and Wnt signaling has a significant function in cancer, few studies have summarized this interaction and its regulation of chondrogenesis. In this review, we focus on MAPK and Wnt signaling, referencing their relationships in various types of cells and particularly to their influence on chondrogenesis and cartilage development. We also discuss the interactions between MAPK and Wnt signaling with respect to cartilage-related diseases such as osteoarthritis and explore potential therapeutic targets for disease treatments.

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Conflict of interest statement

Conflict of Interest

The authors declare no potential conflict of interest.

Figures

Fig. 1
Fig. 1
The best characterized MAPK modules are the ERK pathway, the SAPK/JNK pathway, and the p38 MAPK pathway. The MAPK cascades consist of an MEKK, an MEK, and an MAPK. MEKKs are activated through a large variety of extracellular signals such as growth factors, cytokine factors, and stress. The activated MEKKs can phosphorylate and activate one or several MEKs, which, in turn, phosphorylate and activate a specific MAPK. Activated MAPK phosphorylates and activates various substrates in the cytoplasma and the nucleus of the cell, including transcription factors. These downstream targets control cellular responses (e.g., apoptosis, proliferation, and differentiation).
Fig. 2
Fig. 2
Three Wnt-dependent pathways have been categorized: canonical Wnt/β-catenin and non-canonical Wnt/PCP as well as Wnt/Ca2+ pathways. Canonical Wnt/β-catenin pathway: In cells, with an inactive state of canonical Wnt signaling, cytosolic β-catenin is targeted to proteolytic degradation through phosphorylation by the APC–Axin–GSK3β complex and further ubiquitination through action of βTrCP-dependent E3 ubiquitin ligase complex. On stimulation by Wnt ligands through binding to Fzd receptors and its co-receptor Lrp, Fzd recruits and phosphorates Dsh, and inhibits APC–Axin–GSK3β complex formation by the recruitment and inhibition of GSK3β. Consequently, β-catenin can accumulate in the cytoplasm and enter the nucleus, activating transcription of target genes through association with the Lef1/Tcf transcription factor family. Non-canonical Wnt/Ca2+ pathway: Interaction of Wnt ligands with Fzd receptors can lead to an increase in intracellular calcium level, through possibly the activation of phospholipase C (PLC). Intracellular calcium will subsequently activate Ca2+/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC) in cells, as well as the transcription factor NFAT. This pathway is particularly important for convergent-extension movements during gastrulation. Additionally, Fzd receptors can also activate JNK, promoting expression of specific genes through activation of AP-1. Non-canonical Wnt/PCP pathway: This pathway is characterized by an asymmetric distribution of Fzd and related receptors, resulting in the polarization of the cell. Also, Wnt-signaling activates Cdc42, RhoA, and Rac1 leading to cytoskeleton rearrangement. Rac1 can also activate JNK, activating specific gene transcription through modulation of the AP-1 protein complex.
Fig. 3
Fig. 3
Influence of canonical Wnt signals on the MAPK pathway. Wnt3a treatment activated the Raf-1-MEK-ERK cascade (Yun et al. 2005) and the JNK pathways (Bikkavilli et al. 2008a). Furthermore, Wnt3a activation of activator protein-1 (AP-1) was blocked by the inhibition of JNK with SP600125 and by the inhibition of AP-1 with N-acetyl-L-cysteine and nordihydroguaiaretic acid (Hwang et al. 2005). In C3H10T1/2 cells, AP-1 was activated by ERK1/2 (Seghatoleslami et al. 2003). In totipotent mouse F9 teratocarcinoma cells, canonical Wnt-β-catenin-JNK signaling was found to be activated by G-proteins, which propagated the signals downstream through Dishevelled (Dsh) isoforms; suppression of Dsh-1 or Dsh-3 abolished Wnt3a activation of JNK (Bikkavilli et al. 2008a). In addition to JNK and ERK, p38 MAPK was strongly activated by Wnt3a and the activated p38 MAPK regulated canonical Wnt-β-catenin signaling through regulation of GSK3β. Chemical inhibitors of p38 MAPK (SB203580) and expression of a dominant negative (DN)-version of p38 MAPK attenuated Wnt3a-induced accumulation of β-catenin, Lef/Tcf-sensitive gene activation, and primitive endoderm formation (Bikkavilli et al. 2008b).
Fig. 4
Fig. 4
Influence of non-canonical Wnt signals on the MAPK pathway. In mouse F9 teratocarcinoma embryonal cells, a strong activation of p38 MAPK was observed in response to Wnt5a and treatment with SB203580 effectively abolished the ability of Wnt5a’s stimulatory effects (Ma and Wang 2007). Wnt5a was also found to promote ERK1/2 phosphorylation, enhancing endothelial cell survival and proliferation (Masckauchán et al. 2006), and the expression of Wnt5a blocked canonical Wnt signaling in endothelial cells (Masckauchán et al. 2006) and other cell types (Topol et al. 2003). However, non-canonical Wnt signaling more commonly functions through the Wnt-JNK pathway. Activation of Wnt5a signaling by IL-1β induced the expression of MMPs via the JNK pathway in rabbit temporomandibular joint (TMJ) condylar chondrocytes, whereas blockage of JNK signaling impaired the Wnt5a-induced up-regulation of MMPs (Ge et al. 2009). Wnt5a increased chondrocyte differentiation at an early stage through CaMK/NFAT-dependent induction of Sox9 while repressing chondrocyte hypertrophy via NF-κB-dependent inhibition of Runx2 expression (Bradley and Drissi 2010). Wnt5b activated JNK, a component of the planar cell polarity pathway, contributed to an increase in cellular migration while Wnt5b also decreased cell-cell adhesion through an activation of Src and subsequent cadherin receptor turnover (Bradley and Drissi 2011).
Fig. 5
Fig. 5
Influence of MAPK signals on the Wnt pathway. Expression of constitutively active MKK6, an upstream activator of p38 MAPK, in 293T cells increased the expression of β-catenin proteins through direct phosphorylation of GSK3β protein both in vitro and in vivo; this phosphorylation was blocked by SB203580 or the knock-out (KO) of MKK3 and MKK6 (Thornton et al. 2008). Members of MAPKs such as ERK1/2, p38 MAPK, and JNK contributed to the phosphorylation of PPPS/TP clusters of endogenous LDL-related protein 6 (LRP6) phosphorylation, stimulating Wnt/β-catenin expression. Rac1, a small signaling G protein, could activate JNK2 to phosphorylate β-catenin (Wu et al. 2008). In Xenopus embryos, activation of JNK antagonized the canonical Wnt pathway through activating the nuclear export of β-catenin rather than maintaining its cytoplasmic stability (Liao et al. 2006). Receptor tyrosine kinase (RTK) systems facilitated Wnt/β-catenin signaling by the PI3K/AKT pathway through inhibiting GSK3 activities (Dailey et al. 2005); RTKs could also phosphorylate β-catenin through involving ERK/LRP6 pathways to activate Wnt/β-catenin signaling (Krejci et al. 2012).
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References

    1. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004;18:1072–1087. - PMC - PubMed
    1. Badger AM, Griswold DE, Kapadia R, Blake S, Swift BA, Hoffman SJ, Stroup GB, Webb E, Rieman DJ, Gowen M, Boehm JC, Adams JL, Lee JC. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum. 2000;43:175–183. - PubMed
    1. Beier F, LuValle P. Serum induction of the collagen X promoter requires the Raf/MEK/ERK and p38 pathways. Biochem Biophys Res Commun. 1999;262:50–54. - PubMed
    1. Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982;30:215–224. - PubMed
    1. Bikkavilli RK, Feigin ME, Malbon CC. G alpha o mediates WNT-JNK signaling through dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells. J Cell Sci. 2008a;121:234–245. - PubMed

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