Page 13 - ISAKOS 2021 Newsletter Volume 1

Although these cells are important because they are the first line of defense against infectious agents, they can cause significant harm to proximal immune and parenchymal cells through the generation of microbicidal agents, including reactive oxygen species (ROS) and proteases, for instance, as well as continuous stimulation of other leukocytes4. Conversely, the M2 subtype has been well-linked to Th2 lymphocyte responses, displaying hyporeactivity to the aforementioned M1-type ligands, thus being considered anti-inflammatory. The M2 phenotype switch takes place at later stages, following the induction of the M1 response. This biological event usually occurs after the engulfment of apoptotic neutrophils in addition to other signals. This stimulates macrophages to downregulate their own pro- inflammatory roles and shift their properties toward the resolution phase of the inflammatory cascade and, ultimately, tissue repair4.
Conceptualization of Meta-Inflammation
Irregular macrophage polarization can contribute to obesity-induced insulin resistance (IR), one of the well characterized clusters for MS and meta-inflammation. For instance, the macrophages localized in the adipose tissue of lean individuals are generally shifted toward the M2 phenotype, being predominantly anti-inflammatory in nature2. The inflammatory stress caused by obesity results in the recruitment of pro-inflammatory M1-like macrophages into the adipose tissue. In fact, possible contributions of pro-inflammatory macrophages to obesity-associated inflammation and IR have been proposed. As an example, macrophages residing in adipose tissue dampen the insulin response in adipocytes during obesity and augment inflammatory reactions via the dysregulated production of more pro-inflammatory cytokines2. To make matters worse, obesity-induced metabolic stress not only allows the infiltration of M1 macrophages but also causes the M2 macrophages to switch back to their former role2.
These circumstances are particularly detrimental to certain organs and tissues, especially those of a musculoskeletal nature. To illustrate, a very recent study1 investigated the association between chronic low-grade inflammation (metabolic syndrome) and the harmful subchondral bone alterations during the onset of osteoarthritis (OA). The authors reported that large molecules may traverse between both bone and cartilage compartments in both healthy and diseased joints. This opens up the possibility for dysregulated circulatory “inflammokines” (inflammatory cytokines) to infiltrate the joint compartment and interfere with regular cell signaling and metabolic activity, causing inflammatory stress. Unresolved cellular stress fragilizes osteochondral integrity, causing the loss of demarcation between bone and articular cartilage, exposing the subchondral bone and its nerves to imbalanced biochemical and biomechanical signals.
Continuous stress promotes additional tissue alterations, establishing a positive feedback loop as a result of multiple unsuccessful attempts to return to cell homeostasis.
Taking the aforementioned facts into consideration, it is important for medical practitioners to prepare the soil, designing interventional strategies to halt inflammation and reestablish tissue homeostasis. This can be achieved by a combination of conservative approaches preceding orthobiologic treatments, as presented in the following section.
Preparing the Soil
In order to reverse a patient’s state of chronic inflammation and prepare the soil, doctors must thoroughly analyze the individual’s health style and apply suitable modifications, especially dietary habits.
Sleep Quality
Often overlooked, sleep quality is an important key factor that must be put in check in order to improve health. Mediators of inflammation can be significantly altered by loss of sleep. The circadian rhythm is, in great part, responsible for a wide variety of functions such as cellular division, migration, metabolism, and other biological processes. The physiological alterations that take place during sleep are believed to promote a favorable microenvironment for stem cells to proliferate, migrate, and differentiate. Such biological events strongly rely on circadian clock genes or other variables, including growth factors, cytokines, and hormones. Melatonin and cortisol, in particular, are released in response to neural optic signals and work cooperatively to regulate many biological functions during sleep. Melatonin appears to enhance osteogenesis and chondrogenesis while inhibiting adipogenesis. Additionally, it may also be protective against oxidative stress-induced apoptosis in mesenchymal stem cells (MSCs), dampening intracellular reactive oxygen species (ROS) production to improve cell viability and secure MSC differentiation into other lineages. With regard to musculoskeletal tissue health, melatonin appears to be highly beneficial because of its capacity to enhance bone alkaline phosphatase levels and mineralization, promote the synthesis of type-I collagen, and increase bone mass and growth. Furthermore, it also may counteract the reduction of cell proliferation by iron overload in bone marrow-derived MSCs upon reversion of the upregulation of p53, ERK, and p38 protein expression in cells.
Hormone Screening
The assessment of specific hormones is another important strategy. Thyroid hormones, for example, are known to have vital roles that influence the biochemical content of cells, such as the enhancement of collagen production in chondrocytes, for instance. Testosterone is another hormone with indispensable functions.
CURRENT CONCEPTS
ISAKOS NEWSLETTER 2021: VOLUME I 11