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  • 6-Chloromelatonin While the apparent complexity of gap junct

    2021-11-24

    While the apparent complexity of gap junction regulation presents challenges, new technologies continue to propel the field forward. Advances in microscopy are increasingly able to capture rapid dynamics at the plasma membrane (e.g., biosensors [67] and lattice light sheet microscopy [100]) and to discern 3 dimensional structures at extremely high resolution (e.g., super-resolution imaging [53], [87] and EM tomography [40], [101]). This rendering of 3-dimensional gap junctions and connexisomes and the spatiotemporal orientation of interacting proteins highlight the interplay of gap junction structure and function. Work involving the manipulation of connexins, especially Cx43, in tissue and organisms show that gap junction biology can affect health and outcomes as shown by work utilizing Cx43 mutant mice [93], [94], [102] or Cx43-targeted reagents [68], [103]. Non-junctional roles for Cx43, particularly its role in the cardiac mitochondria, are expanding our view of this protein. New frameworks and technologies will continue to pave the way to understanding the mechanisms by which gap junctions both sense and shape cellular responses to injury and ultimately, provide new avenues to improve outcomes.
    Transparency document
    Acknowledgements A grant from the National Institutes of Health supported the work presented from the Lampe laboratory (R01GM055632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
    Connexins are pore forming subunits of gap junction (GJ) channels and hemichannels (HCs) that are indispensable for proper development and function of skeletal tissues. HCs are formed by six subunits of connexins (Cx) and allow connections with the extracellular space. HCs embedded in the plasma membranes of adjacent 6-Chloromelatonin form clusters to create the gap junctional plaques that provide pathways for direct intercellular communication via channels that link the cytoplasmic compartments of cells. This type of intercellular communication (GJ channels) permits coordinated cellular activity by direct exchange of second messengers, electrical signals, ions, metabolites, nutrients and other molecules that regulate cell survival, growth and metabolism[1]. Several pathologies including inflammation, cancer and degenerative conditions such as Alzheimer's, osteoarthritis (OA) or osteoporosis have recently been associated with alterations in 6-Chloromelatonin Cx functions. Cx43 is the major Cx protein expressed in developing and mature skeletal tissues including chondrocytes (CHs), synovial cells (SCs) and bone cells (osteocytes, osteoblast and osteoclast) (BCs). However, other members of the Cx family have been reported to be expressed in adult and/or developing cartilage (Cx43, Cx32, Cx46 and Cx45, synovial cells (Cx26, Cx32 and Cx43) and bone cells (Cx43, Cx46, Cx45 and Cx37)[2,3,4]. The close proximity, compensatory mechanisms and evidence of biomechanical and molecular signalling between cartilage, subchondral bone and synovial tissue are suggestive of molecular crosstalk between tissues in the joint[5,6]. Additionally, other joint tissues such as muscle cell-derived factors also affect cartilage homeostasis[7,8]. However, more work is required to understand the molecular communication and responsiveness that regulate functional behaviour of cells in joint tissues both in physiological and pathological conditions, in order to develop effective strategies to combat joint disorders such as OA. Previous results from our laboratory have shown that articular chondrocytes in cartilage are physically connected with distant chondrocytes through cytoplasmic extensions, and cell-to-cell communication occurs through GJ channels predominantly composed of Cx43[9]. Additionally, Cx43 protein is overexpressed in cartilage and synovial tissue of patients with OA[[10], [11], [12]]. An increase in Cx43 protein levels can alter gene expression, cell proliferation, cell signalling and spread signals (cell death and survival) to neighbouring cells. It has also been recently reported that bone cells can exchange miRNAs through GJs or between distant cells and extracellular vesicles (EVs)[13]. This exchange can modify Cx43 abundance or localization, affecting cell perception and response to mechanical, hormonal and pharmacological stimuli[13]. Interestingly, the response to Cx43 GJ channels stimulus, as well as cartilage and bone density, declines with age[[14], [15], [16]], probably contributing to the disruption of the equilibrium that maintains skeletal and joint integrity.