RAGE Signaling in Skeletal Biology

PURPOSE OF REVIEW: The receptor for advanced glycation end products (RAGE) and several of its ligands have been implicated in the onset and progression of pathologies associated with aging, chronic inflammation, and cellular stress. In particular, the role of RAGE and its ligands in bone tissue during both physiological and pathological conditions has been investigated. However, the extent to which RAGE signaling regulates bone homeostasis and disease onset remains unclear. Further, RAGE effects in the different bone cells and whether these effects are cell-type specific is unknown. The objective of the current review is to describe the literature over RAGE signaling in skeletal biology as well as discuss the clinical potential of RAGE as a diagnostic and/or therapeutic target in bone disease. RECENT FINDINGS: The role of RAGE and its ligands during skeletal homeostasis, tissue repair, and disease onset/progression is beginning to be uncovered. For example, detrimental effects of the RAGE ligands, advanced glycation end products (AGEs), have been identified for osteoblast viability/activity, while others have observed that low level AGE exposure stimulates osteoblast autophagy, which subsequently promotes viability and function. Similar findings have been reported with HMGB1, another RAGE ligand, in which high levels of the ligand are associated with osteoblast/osteocyte apoptosis, whereas low level/short-term administration stimulates osteoblast differentiation/bone formation and promotes fracture healing. Additionally, elevated levels of several RAGE ligands (AGEs, HMGB1, S100 proteins) induce osteoblast/osteocyte apoptosis and stimulate cytokine production, which is associated with increased osteoclast differentiation/activity. Conversely, direct RAGE-ligand exposure in osteoclasts may have inhibitory effects. These observations support a conclusion that elevated bone resorption observed in conditions of high circulating ligands and RAGE expression are due to actions on osteoblasts/osteocytes rather than direct actions on osteoclasts, although additional work is required to substantiate the observations. Recent studies have demonstrated that RAGE and its ligands play an important physiological role in the regulation of skeletal development, homeostasis, and repair/regeneration. Conversely, elevated levels of RAGE and its ligands are clearly related with various diseases associated with increased bone loss and fragility. However, despite the recent advancements in the field, many questions regarding RAGE and its ligands in skeletal biology remain unanswered

Evolutionary consequences of behavioral diversity

Iterated games provide a framework to describe social interactions among groups of individuals. Recent work stimulated by the discovery of "zero-determinant" strategies has rapidly expanded our ability to analyze such interactions. This body of work has primarily focused on games in which players face a simple binary choice, to "cooperate" or "defect". Real individuals, however, often exhibit behavioral diversity, varying their input to a social interaction both qualitatively and quantitatively. Here we explore how access to a greater diversity of behavioral choices impacts the evolution of social dynamics in finite populations. We show that, in public goods games, some two-choice strategies can nonetheless resist invasion by all possible multi-choice invaders, even while engaging in relatively little punishment. We also show that access to greater behavioral choice results in more "rugged " fitness landscapes, with populations able to stabilize cooperation at multiple levels of investment, such that choice facilitates cooperation when returns on investments are low, but hinders cooperation when returns on investments are high. Finally, we analyze iterated rock-paper-scissors games, whose non-transitive payoff structure means unilateral control is difficult and zero-determinant strategies do not exist in general. Despite this, we find that a large portion of multi-choice strategies can invade and resist invasion by strategies that lack behavioral diversity -- so that even well-mixed populations will tend to evolve behavioral diversity.Comment: 26 pages, 4 figure

The inevitability of unconditionally deleterious substitutions during adaptation

Studies on the genetics of adaptation typically neglect the possibility that a deleterious mutation might fix. Nonetheless, here we show that, in many regimes, the first substitution is most often deleterious, even when fitness is expected to increase in the long term. In particular, we prove that this phenomenon occurs under weak mutation for any house-of-cards model with an equilibrium distribution. We find that the same qualitative results hold under Fisher's geometric model. We also provide a simple intuition for the surprising prevalence of unconditionally deleterious substitutions during early adaptation. Importantly, the phenomenon we describe occurs on fitness landscapes without any local maxima and is therefore distinct from "valley-crossing". Our results imply that the common practice of ignoring deleterious substitutions leads to qualitatively incorrect predictions in many regimes. Our results also have implications for the substitution process at equilibrium and for the response to a sudden decrease in population size.Comment: Corrected typos and minor errors in Supporting Informatio

Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress

poster abstractIncreased oxidative stress, such as with excess of glucocorticoids (GC) or during aging, has been associated with endoplasmic reticulum (ER) stress, due to accumulation of misfolded or unfolded proteins, leading to cellular apoptosis. The double-stranded RNA-activated protein kinase-like ER kinase (PERK) is activated to alleviate ER stress and phosphorylates the eukaryotic translation initiation factor 2 alpha subunit (eIF2α). Phosphorylated eIF2α in turn inhibits global protein translation to provide time to the ER to recover from the unfolded protein load, promoting cell viability. We hypothesized that the pro-apoptotic effect of GC on osteoblasts and osteocytes are at least in part due to induction of ER stress. To test this hypothesis, we used MLO-Y4 osteocytic cells, OB-6 osteoblastic cells, and primary osteoblastic cells derived from neonatal murine calvaria. We found that the synthetic GC dexamethasone (DEX) significantly increased the percentage of apoptotic cells in cultures of MLO-Y4, OB-6, and primary osteoblastic cells. Similarly, the specific ER-stress inducing agents brefeldin A, an inhibitor of ER-golgi apparatus vesicle transport, and tunicamycin, a protein glycosylation inhibitor, significantly increased OB-6 cell apoptosis. We then tested the effect of salubrinal, an agent that protects against ER stress by inhibiting the dephosphorylation of eIF2α, on bone cell apoptosis. Salubrinal blocked apoptosis induced by the ER stressors brefeldin A and tunicamycin in OB-6 cells. Salubrinal was also effective in blocking apoptosis induced by DEX in MLO-Y4, OB-6 and primary osteoblastic cells. Optimal responses were found at 10 μM salubrinal, after either 6 or 24 h. Guanabenz, another inhibitor of eIF2α dephosphorylation, also blocked DEX and tunicamycin-induced apoptosis of primary osteoblastic cells. Furthermore, addition of DEX to mineralizing OB-6 or primary osteoblastic cells markedly decreased mineral deposition and hydroxyapatite formation. In contrast, treatment with guanabenz increased mineralization of OB-6 cell cultures and prevented the inhibitory effect of DEX. We conclude that part of the pro-apoptotic actions of GC on osteoblastic cells are mediated through ER stress and that interventions that prevent dephosphorylation of eIF2α could potentially prevent the deleterious effects of GC on bone

Cx43 and mechanotransduction in bone

Bone adaptation to changes in mechanical stimuli occurs by adjusting bone formation and resorption by osteoblasts and osteoclasts, to maintain optimal bone mass. Osteocytes coordinate the actions of these cells on the bone surface by sensing mechanical forces and producing cytokines that increase or prevent osteoblast and osteoclast differentiation and function. Channels formed by connexins (Cxs) and, in particular, connexin 43 (Cx43) in osteoblasts and osteocytes are central part of this mechanism to control bone mass. Cx43 hemichannels are opened by fluid flow and mediate the anti-apoptotic effect of mechanical stimulation in vitro, suggesting that Cx43 participates in mechanotransduction. However, mice lacking Cx43 in osteoblasts and/or osteocytes show an increased anabolic response to loading and decreased catabolic response to unloading. This evidence suggests that Cx43 channels expressed in osteoblastic cells are not required for the response to mechanical stimulation, but mediate the consequence of lack thereof. The molecular basis of these unexpected responses to mechanical stimulation is currently under investigation

Preventing Successor Liability for Defective Products: Safeguards for Acquiring Corporations

In recent years, many courts have determined longstanding limitations on successor liability to be insufficiently sensitive to the compensation needs of products liability claimants. In response, courts in several jurisdictions have eroded traditional corporate law immunities to successor liability for defective products. Although this liberalization of the principles of successor liability has expanded the range of potential defendants in many tort lawsuits, the expansion of liability has caused an increase in uncertainty in corporate transactions, and an increase in complex legal and logistical maneuvering to avoid the growing liability web. This Article seeks to outline the expansion of successor liability in the products area, note the negative implications of that expansion, and identify mechanisms to prevent the attachment of successor liability under both the traditional and expanded regimes. The Article also prescribes a statutory alternative to create much needed stability and certainty in this area through a straightforward allocation of liabilities between purchasers and sellers

Рефрактерный септический шок (часть 1)

Refractory septic shock develops in 6–7% of sepsis patients with short-term lethality rate of more than 50%. It is necessary to assess the effectiveness of intensive therapy methods used in this case.The objective of the review: to analyze publications on the intensive care of refractory septic shock.Results. 56 studies published in the period from January 1, 1990 to September 1, 2020 were analysed, they reflect the effectiveness of some methods used for management of refractory septic shock (treatment of the underlying disease, liquid bolus, the use of norepinephrine, adjuvant therapy, management of metabolic acidosis). The second part of this article will reflect the evaluation of the effectiveness of other approaches to the treatment of this complication.Рефрактерный септический шок развивается у 6‒7% пациентов с сепсисом с краткосрочным показателем летальности более 50%. Существует объективная потребность в оценке эффективности применяемых в этом случае методов интенсивной терапии.Цель обзора: анализ данных литературы, посвященных интенсивной терапии рефрактерного септического шока.Результаты. Проведен анализ 56 исследований, опубликованных в период с 1 января 1990 г. по 1 сентября 2020 г., в которых отражена эффективность некоторых методов, применяемых при рефрактерном септическом шоке (лечение основного заболевания, жидкостный болюс, применение норадреналина, адъювантной терапии, коррекции метаболического ацидоза). Оценка эффективности других подходов, также имеющих место при лечении этого осложнения, будет отражена во второй части этой статьи

Рефрактерный септический шок (часть 2)

Refractory shock is the shock that does not respond to vasopressor therapy. Refractory shock with a short-term mortality rate of more than 50% is diagnosed in 6-7% of critically ill patients. There is an objective need to Investigate methods of intensive therapy for refractory septic shock.The objective of the study: to analyze literature data on the intensive care of refractory septic shock.Results. The second part of the article analyzes 37 studies, both Russian and foreign ones devoted to the intensive care of refractory shock. At present, based on the analysis of the publication, it is impossible to draw reasonable conclusions about the advantage of one or another method of intensive therapy for refractory shock (veno-venous hemofiltration, the use of angiotensin II and vasopressin, as well as methylene blue, vitamin B12, ECMO) over basic therapy.Рефрактерный шок – это шок, не отвечающий на терапию вазопрессорами. У 6‒7% пациентов в критическом состоянии диагностируется рефрактерный шок с краткосрочным показателем летальности более 50%. Существует объективная потребность в изучении методов интенсивной терапии рефрактерного септического шока.Цель исследования: анализ данных литературы по интенсивной терапии рефрактерного септического шока.Результаты. Во второй части статьи проведен анализ 37 отечественных и иностранных исследований, посвященных интенсивной терапии рефрактерного шока. В настоящее время на основании анализа литературы нельзя сделать обоснованные выводы о преимуществе того или иного метода интенсивной терапии рефрактерного шока (вено-венозной гемофильтрации, применения ангиотензина II и вазопрессина, а также метиленового синего, витамина В12, ЭКМО) перед базовой терапией