Acute and chronic stress in bone repair: an updated approach from the Neurosciences.
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The physiological molecular mechanisms associated with the response to acute and chronic stress allow us to understand the changes that these can produce in the various tissues of the body. Various investigations highlight the role of chronic stress in the development of dysfunctions that affect body balance; However, it must be considered that the mechanisms related to acute stress can also influence the development of pathologies and the progression of the deleterious manifestations of chronic stress. On the other hand, one of the most studied tissues in recent years has been bone tissue, since it is influenced by nervous, endocrine and immunological factors. This paper seeks to analyze the neuroscientific bases of the molecular mechanisms of stress and their relationship in the bone repair process. Therefore, a literature search was carried out in the Pubmed, Scopus and ScienceDirect databases. Concluding that stress modifies the release of neurotransmitters, the action of the autonomic nervous system, the release of corticotropic hormones and the activity of various cytokines; which leads to the imbalance of the regulation and repair processes of the bone tissue subjected to load or injury.
Key words: acute stress, chronic stress, bone regeneration, bone tissue.
Stress is defined as a set of physiological responses of the body to a stimulus, adverse factor or to some restriction that an individual suffers(1). In health sciences, stress can be classified as acute and chronic, which generate physiological variations in the individual by altering the neuro-immuno-endocrine axis as a whole(2). In the face of stress, it has been shown that there is a disturbed response of endogenous endocrine mediators, which have various effects on the regulation of tissue homeostasis(3); a modification of the release of neuropeptides and neuromodulators from the sympathetic-adrenal-medullary and noradrenergic systems of the locus coeruleus nucleus in the brain stem(4) is also generated.
On the other hand, stress can impact the physiology of many body tissues in multiple ways. One of the tissues that could be directly or indirectly affected by the effects of stress is bone. When an injury occurs or a surgical procedure is performed, the bones present an endogenous response that allows the reestablishment of integrity without an increase in volume, called bone repair(5). Even though bone has this intrinsic repair capacity, there are factors that could modify it to the point of deterioration or make it insufficient, such as hormonal factors (cortisol and adrenaline)6 and changes in the immuno-endocrine
Various studies in humans and experimental animals indicate a relationship between stress, mainly chronic stress, and the degree of bone loss(9,10). There are preclinical models with senile mice that relate chronic stress with the acceleration in the development of osteoporosis(11); nevertheless, it would be important to determine what would be the function that acute stress exerts on the molecular changes that could affect bone repair processes in the event of an injury, as well as it is pertinent to know how these processes generated in acute stress are the basis for the development of chronic stress and its neuro-immuno-endocrine changes.
For these reasons, this research seeks to carry out an updated review, with a neuroscience approach, on the various molecular pathways related to acute and chronic stress, to recognize the role that acute stress exerts on the molecular changes that could affect bone repair processes in the face of injury. It is also pertinent to know how these processes generated in acute stress are the basis for the development of chronic stress and its neuroimmunoendocrine changes.
Stress: types and mechanisms of action
Stress is defined by the World Health Organization (WHO) as the set of physiological reactions that prepares the body for action(12). In general terms, it is a biological warning system necessary for survival(13). The physiological stress response can be positive and even pro-adaptive in the face of some adverse situation or aggression, but this response can change towards a negative or maladaptive conformation if the stressful agent is permanent or if the individual has some altered physiological or pathological condition(14). Stress can be divided into acute and chronic, both with determining effects on the individual and interrelated for the joint development of specific molecular mechanisms that will modify the homeostatic processes of the organism.(15)
Acute stress occurs due to the transitory action of a stressor, unlike chronic stress which is produced by a continuous difficulty that may or may not represent a constant threat to life(14). Faced with the development of acute stress, there is a rapid activation of the sympathetic nervous system, which triggers the production of endogenous catecholamines and, in parallel, a progressive activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, promoting the progressive and sustained release of cortisol and corticosterone(16-18); It is these molecules, which, being lipophilic in nature, have intracellular receptors, and despite being released by acute stressors, they can continue to generate genomic-type effects at the cellular level for days or months(19) A hormone also released in situations of acute stress is dehydroepiandrosterone (DHEA), which can modify cellular processes due to its ability to bind to GABAa receptors, while corticosteroids do so to GR and MR receptors.(20)
At the level of the cerebral neocortex, acute-type stress allows the increased release of glutamate into the system; such that stress-induced corticosteroids act on GR/MR receptors, promoting increased mobilization of glutamate vesicles in neurons and increased neurotransmitter release via rapid non-genomic mechanisms of synapsin I phosphorylation in the presynaptic membranes.(14)
Studies carried out in birds highlight the modifying role of acute stress on the immune response by increasing the transcription levels of genes for proinflammatory cytokines such as IL-6, IL-17, and TNF-?21. Other studies in rats show that exposing them to an acute stressor can promote the activation of macrophages in the cerebral vasculature, increase serum levels of IL-6, activation of microglia, and generate the highest expression of COX-2 and prostaglandin E2 in the central nervous system(22,23). Studies in humans subjected to acute stress show a greater expression of cytotoxic NK cells and monocytes at the peripheral level associated with greater activity of cortisol and catecholamines, while a decrease in B and T lymphocytes was evidenced(24). Finally, we can say that stress not only affects the immune response at the level of the central nervous system, but also at the peripheral level, this immune response being regulated by the release of corticosterone in the individual(25); For instance, in investigations of acute stress induction in rats, it is possible to show that there is an increase in the proinflammatory phenotype of hepatic peripheral macrophages, an increase in the expression of induced nitric oxide synthase and an increase in the activation of vitamin D.(26)
Meanwhile, in chronic stress, neuroplastic changes are produced in response to a stressor that was initially acute, but then became sustained and overwhelmed the regulatory feedback mechanisms, generating basic structural and functional changes for the generation of unfavorable events for the patient. individual(27). Studies in mice show the relationship between chronic stress and the development of structural and functional abnormalities of the amygdala, cortex, and hippocampus, reducing the levels of glutamate, acetylaspartate, and choline, but increasing the levels of creatine and myo-inositol, which would generate cell exhaustion; as well as the permanent and uncontrolled activation of the HPA axis, triggering hyperglycemia due to the constant release of catecholamines and corticosteroids(28,29).
Some studies even relate chronic stress to a marked reduction in dopamine and serotonin levels in mice with the induction of neurodegenerative diseases such as Parkinsons, accelerating the progression of the disease.(30)
An important consequence generated by chronic stress is an unregulated and expressed pro-inflammatory response with an increase in blood and nerve tissue of proinflammatory cytokines, such as IL-1? and interferon ? (IFN-?), which generates an activation of microglia and macrophages to generate compensatory events of neuroprotection(31). On the other hand, studies in rats indicate that acute stressors can increase the levels of mRNA for the NLRP3 protein, and induce the chronic formation of this protein, which participates in the generation of the inflammasome and the long-term increased production of inflammatory mediators. such as IL-1?, IL-6, TNF, and NF-?B, producing proinflammatory events that accelerate the unfavorable effects of chronic stress.(32)
Stress on bone repair
It can be considered that there is an evolutionary relationship between stress and bone tissue. During the evolution of vertebrates, the bone and its involved endocrine processes have played an important role in the survival of the individual, since they have allowed, when faced with the stress of lack of food or the stalking of some predator, to develop neuroendocrine mechanisms between the bone and the sympathetic nervous system that allow an adequate response to stressful situations(33,34). Likewise, bones are very susceptible to injury due to the load and movement function they develop in the body; and even more so in a stress situation, it is pertinent to be clear about how the reparative response of the bone tissue will be presented, since the homeostasis of the individual fundamentally depends on it.
Bone repair is understood as the endogenous healing capacity of human bones, and is characterized by the development of several phases: an inflammatory phase, a soft callus formation phase, a cartilage replacement phase (replacement by bone callus), and a bone remodeling phase.(5)
As detailed above, before the generation of an acute stressor there will be a significant release of glutamate in the nervous system(14); This release of the neurotransmitter can spread throughout the system and enter the osteoblasts through the GLAST transporter, generating the inhibition of the cytoplasmic enzyme gamma-glutamyl carboxylase (GGCX), and the consequent formation and release of decarboxylated osteocalcin (bioactive) in a higher proportion. In an immediate adverse situation, decarboxylated osteocalcin can induce the release of IL-6 in the GPRC6A receptors of the myofibers of the muscular system, which can send signals to osteoblasts to promote the formation of more bioactive osteocalcin, in a feedback process positive that triggers the optimal and sustained mineralization of the bone extracellular matrix (ECM-O) in a situation of musculoskeletal work induced by situations of acute stress.(33,35,36)
On the other hand, osteocalcin released by acute stressors, by binding to its GPRC6A receptors at the level of autonomic neurons, can inhibit the expression of genes that encode the formation of choline-acetyl transferase (ChAT), choline transporter type 1 (ChT1) and choline transporter type 1 (ChT1). vesicular acetylcholine transporter type 1 (VAChT1), which are important proteins in the synthesis and recycling of acetylcholine (ACh) in peripheral tissues, reducing the action of acetylcholine and promoting autonomic balance in favor of the sympathetic adrenergic system(34); remembering that this increase in adrenergic activity is one of the events that also develop in response to the exposure of individuals to acute stress(17). The activity on beta and alpha-adrenergic receptors can promote the growth of bone mass by increasing the expression of the transcription factor NFIL3 / E4BP4.(37)
Cytokines are important messengers in the functioning of the neuroimmunoendocrine axis, and their relationship with stress and bone repair processes continues to be studied today. One of the most important cytokines in these processes is IL-6, since, as mentioned above, it participates in the formation of bioactive osteocalcin by the osteoblast in the face of the musculoskeletal response in situations of acute stress(35). Many preclinical studies also highlight the important role of IL-6 in the activation of osteoclasts when there is an injury or fracture in the bone(38). IL-6 can exert a great diversity of functions in the bone depending on the situation that is presenting itself. In the event of a bone injury, the amounts of IL-6 increase rapidly, which would lead to an increase in the recruitment of macrophages and greater differentiation into osteoclasts(39); Likewise, it has been determined that in the face of an increase in the amounts of corticosteroids in the body, which may be elevated in situations of chronic stress or in pathological states, IL-6 signaling can generate induction in the expression of RANKL, promoting osteoclastogenesis and bone tissue resorption.(40)
During chronic stress there is a significant increase in the concentrations of endogenous corticosteroids, which have been shown in diverse experimental studies in mice to regulate bone repair processes, with glucocorticoids being important suppressors of osteoblastogenesis and inducers of osteoblastic apoptosis(41); Associated with this, glucocorticoids participate as positive regulators of RANKL and macrophage colony-stimulating factor (M-CSF), but it is also important to highlight their role as negative regulators of Osteoprogeterin (OPG) expression, which would lead to a greater osteoclastic activity with less activity of the osteoblast function.(42)
Stress is a physiological response to a stressor agent that can affect it temporarily (acute stress) or sustained (chronic stress) throughout the development of an individual. Acute stress normally produces beneficial changes in bone tissue, such as increased bone mass, facilitating turnover processes mediated by bone resorption and apposition events. This acute stress also produces intracellular changes in bone-forming cells, generating long-term consequences that favor the development of detrimental effects in the face of chronic stressors. The deleterious changes that the bone undergoes due to chronic stress, and the changes generated by acute stress, are developed by modifications in the immuno-neuro-endocrine axis. The modifications generated by stress in the release of neurotransmitters, corticosteroid hormones and the variations in the formation of proinflammatory and anti-inflammatory cytokines are the basis for understanding the changes that can occur in the process of bone homeostasis and repair.
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