Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metabolism, stress response and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase kinase, a MAPK kinase, and a MAPK. In turn MAPKs phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: ribosomal-S6-kinases (RSK1-4), mitogen- and stress-activated kinases (MSK1-2), MAPK-interacting kinases (MNK1-2), MAPKAPK-2 (MK2), MAPKAPK-3 (MK3), and MAPKAPK-5 (MK5). The role of these MAPKAPKs in inflammation will be reviewed.

https://www.mdpi.com/2073-4425/4/2/101/pdf

The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated in response to a wide range of extracellular signals. As a consequence, it can generate many different biological effects that depend on the stimulus and on the activated cell type. Therefore, this pathway has been found to regulate many aspects of tissue development and homeostasis. Recent work with the aid of genetically modified mice has highlighted the physiological functions of this pathway in skeletogenesis and postnatal bone maintenance. In this review, emphasis is given to the roles of the p38 MAPK pathway in chondrocyte, osteoblast and osteoclast biology. In particular, we describe the molecular mechanisms of p38 MAPK activation and downstream targets. The requirement of this pathway in physiological bone development and homeostasis is demonstrated by the ability of p38 MAPK to regulate master transcription factors controlling geneses and functions of chondrocytes, osteoblasts and osteoclasts.

Focus on the p38 MAPK signaling pathway in bone development and maintenance.

p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.

/pdf/selective-inhibition-of-the-p38a-mapk-mk2-axis-inhibits-4dmugewwad.pdf

Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals.

Inflammation is normally a fast and transient response to microbial invaders or sterile damage and has to be stringently controlled. The closely-related mitogen-activated protein kinase-activated protein kinases MK2 and MK3 are involved in both up- and down-regulation of inflammation in mammals and govern the inflammatory response at different regulatory levels of gene expression and with different kinetics. In conjunction with their activator MAP kinase p38, MK2 and MK3 stimulate the transcription of immediate-early genes including that of the mRNA-binding protein tristetraprolin (TTP). TTP competes with the constitutively expressed protein human antigen R in binding to the mRNA destabilizing adenylate-uridylate -rich element. MK2 and MK3 also regulate the activity of TTP by direct phosphorylation, determine stability and stimulate the translation of cytokine mRNAs. In addition, TTP controls its own re-synthesis via stability and translation of its mRNA in a phosphorylation-dependent manner. This results in a complex scenario of gene expression and guarantees fast up-regulation and intrinsic feedback control of the inflammatory response of macrophages. Inhibition of MK2/3 by small-molecule pharmaceutical inhibitors is an emerging strategy to manipulate the inflammatory response as a therapeutic option. This strategy could display advantages over the direct inhibition of MAP kinase p38.

What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition.

Osteoclasts (OCs) are bone-resorptive cells critical for maintaining skeletal integrity through coupled bone turnover. OC differentiation and activation requires receptor activator of NF-kB ligand (RANKL) signaling through the p38 MAPK pathway. However the role of the p38 MAPK substrate, MAPK-activated protein kinase 2 (MK2), is not clearly delineated. Within the bone marrow exists a specific subpopulation of defined osteoclast progenitor cells (dOCPs) with surface expression of B220-Gr1-CD11blo/-CD115+ (dOCPlo/-). In this study, we isolated dOCPs from male and female mice to determine sex-specific effects of MK2 signaling in osteoclastogenesis (OCgen). Male Mk2-/- mice display an increase in the dOCPlo cell population when compared to Mk2+/+ mice, while female Mk2-/- and Mk2+/+ mice exhibit no difference. Defined OCPs from male and female Mk2+/+ and Mk2-/- bone marrow were treated with macrophage colony stimulation factor (M-CSF) and RANKL cytokines to promote OCgen. RANKL treatment of dOCPlo cells stimulated p38 and MK2 phosphorylation. Tartrate-resistant acid phosphatase (TRAP) assays were used to quantify OC number, size, and TRAP enzyme activity post-RANKL stimulation. MK2 signaling was critical for male dOCPlo OCgen, yet MK2 signaling regulated OCgen from female dOCP- and CD11bhi subpopulations as well. The functional gene, Ctsk, was attenuated in both male and female Mk2-/- dOCPlo-derived OCs. Conversely, MK2 signaling was only critical for gene expression of pre-OC fusion genes, Oc-stamp andTm7sf4, in male OCgen. Therefore, these data suggest there is a sexual dimorphism in MK2 signaling of OCP subpopulations.

/pdf/sexual-dimorphism-in-mapk-activated-protein-kinase-2-mk2-5b9mvzjl8t.pdf

Sexual Dimorphism in MAPK-Activated Protein Kinase-2 (MK2) Regulation of RANKL-Induced Osteoclastogenesis in Osteoclast Progenitor Subpopulations.

The objective of this study was to investigate the role of the serine-threonine kinase mitogen-activated protein kinase 2 (MK2) in bone homeostasis. Primary bone cell cultures from MK2(+/+) and MK2(-/-) mice were assessed for osteoclast and osteoblast differentiation, bone resorption, and gene expression. Bone architecture of MK2(+/+) and MK2(-/-) mice was investigated by micro-computed tomography and histomorphometry. Ovariectomy was performed in MK2(+/+) and MK2(-/-) mice to assess the role of MK2 in postmenopausal bone loss. Osteoclastogenesis, bone resorption, and osteoclast gene expression were significantly impaired in monocytes from MK2(-/-) compared to MK2(+/+) mice. Mechanistically, loss of MK2 causes impaired DNA binding of c-fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) to tartrate-resistant acid phosphatase (TRAP) and the calcitonin receptor gene promoter. In addition, MK2(-/-) mice showed an age-dependent increase in trabecular bone mass and cortical thickness, fewer osteoclasts, and lower markers of bone resorption than MK2(+/+) mice. Furthermore, MK2(-/-) mice were protected from ovariectomy-induced bone loss. Osteoblastogenesis and bone formation were unchanged in MK2(-/-) mice, whereas osteoblast expression of osteoprotegerin (OPG) and serum levels of OPG were higher in MK2(-/-) than in MK2(+/+) mice. Loss of MK2 effectively blocks bone resorption and prevents the development of postmenopausal bone loss. Small-molecule inhibitors of MK2 could thus emerge as highly effective tools to block bone resorption and to treat postmenopausal bone loss.

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1002/jbmr.1816

Mitogen-activated protein kinase 2 regulates physiological and pathological bone turnover

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9108971

Incidence and predictors of cardiac arrhythmias in patients with COVID-19 induced ARDS

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Mitogen-activated protein kinase 2 regulates physiological and pathological bone turnover

Incidence and predictors of cardiac arrhythmias in patients with COVID-19 induced ARDS