JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing

Abstract

In healthy individuals, the healing of soft tissues such as skin after pathological insult or post injury follows a relatively predictable and defined series of cell and molecular processes to restore tissue architecture and function(s). Healing progresses through the phases of hemostasis, inflammation, proliferation, remodeling, and concomitant with re-epithelialization restores barrier function. Soft tissue healing is achieved through the spatiotemporal interplay of multiple different cell types including neutrophils, monocytes/macrophages, fibroblasts, endothelial cells/pericytes, and keratinocytes. Expressed in most cell types, c-Jun N-terminal kinases (JNK) are signaling molecules associated with the regulation of several cellular processes involved in soft tissue wound healing and in response to cellular stress. A member of the mitogen-activated protein kinase family (MAPK), JNKs have been implicated in the regulation of inflammatory cell phenotype, as well as fibroblast, stem/progenitor cell, and epithelial cell biology. In this review, we discuss our understanding of JNKs in the regulation of cell behaviors related to tissue injury, pathology, and wound healing of soft tissues. Using models as diverse as Drosophila, mice, rats, as well as human tissues, research is now defining important, but sometimes conflicting roles for JNKs in the regulation of multiple molecular processes in multiple different cell types central to wound healing processes. In this review, we focus specifically on the role of JNKs in the regulation of cell behavior in the healing of skin, cornea, tendon, gingiva, and dental pulp tissues. We conclude that while parallels can be drawn between some JNK activities and the control of cell behavior in healing, the roles of JNK can also be very specific modes of action depending on the tissue and the phase of healing.

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

“…2010; Koch et al, 2015), as well as many other inflammatory diseases (Thalhamer et al, 2008;Nikoloudaki et al, 2020). CFB may also represent a therapeutic target in RA, as CFB deficient mice (CFB -/-) are highly resistant to CIA and CAIA and have a decreased CII-specific IgG antibody response in CIA (Hietala et al, 2002;Banda et al, 2006).…”

“…These mapping results are supported by our previous kinase screening, which demonstrated that TRYP-Ox had affinity for all three JNKs, with the highest affinity for JNK1 (150 nM) and JNK3 (275 nM) ( Schepetkin et al., 2019 ). Indeed, a number of studies have shown that JNKs play an important role in RA ( Han et al., 2001 ; Bogoyevitch et al., 2010 ; Koch et al., 2015 ), as well as many other inflammatory diseases ( Thalhamer et al., 2008 ; Nikoloudaki et al., 2020 ). CFB may also represent a therapeutic target in RA, as CFB deficient mice (CFB -/- ) are highly resistant to CIA and CAIA and have a decreased CII-specific IgG antibody response in CIA ( Hietala et al., 2002 ; Banda et al., 2006 ).…”

Involvement of JNK1 in Neuronal Polarization During Brain Development

“…Different JNKs phosphorylate a wide arrange of nuclear and cytosolic substrates in serine/threonine residues, followed by proline residue, thereby underpinning their role in critical physiological processes that include neuronal functions and immunological responses, together with embryonic and postnatal development [4][5][6]. This is evidence of the highly differentiated regulatory functions of JNK isoforms [7].…”

Comprehensive Review of Hybrid Collagen and Silk Fibroin for Cutaneous Wound Healing

“…In turn, JNK will phosphorylate another two residues known as serine 63 and serine 73. Furthermore, it will further induce the production of downstream target genes such as plasminogen activator inhibitor-I, which plays a vital role in cell migration [ 60 ]. Martínez-Mora and co-workers (2012) [ 22 ] proved that a very minimal amount, approximately 0.4% of fibroin, could accelerate the production of genes involved in cell migration.…”