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

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

Magnet Laboratory Research

Contains reports on three research projects

Evolution on a Rugged Landscape:Pinning and Aging

Population dynamics on a rugged landscape is studied analytically and numerically within a simple discrete model for evolution of N individuals in one-dimensional fitness space. We reduce the set of master equations to a single Fokker-Plank equation which allows us to describe the dynamics of the population in terms of thermo-activated Langevin diffusion of a single particle in a specific random potential. We found that the randomness in the mutation rate leads to pinning of the population and on average to a logarithmic slowdown of the evolution, resembling aging phenomenon in spin glass systems. In contrast, the randomness in the replication rate turns out to be irrelevant for evolution in the long-time limit as it is smoothed out by increasing ``evolution temperature''. The analytic results are in a good agreement with numerical simulations.Comment: 4 pages, 3 figures, submitted to Phys. Rev. Let

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (−33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (−25%), in line with reduced fat (−58%) and lean (−17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy

Kripke Semantics for Martin-L\"of's Extensional Type Theory

It is well-known that simple type theory is complete with respect to non-standard set-valued models. Completeness for standard models only holds with respect to certain extended classes of models, e.g., the class of cartesian closed categories. Similarly, dependent type theory is complete for locally cartesian closed categories. However, it is usually difficult to establish the coherence of interpretations of dependent type theory, i.e., to show that the interpretations of equal expressions are indeed equal. Several classes of models have been used to remedy this problem. We contribute to this investigation by giving a semantics that is standard, coherent, and sufficiently general for completeness while remaining relatively easy to compute with. Our models interpret types of Martin-L\"of's extensional dependent type theory as sets indexed over posets or, equivalently, as fibrations over posets. This semantics can be seen as a generalization to dependent type theory of the interpretation of intuitionistic first-order logic in Kripke models. This yields a simple coherent model theory, with respect to which simple and dependent type theory are sound and complete

Syndrome of acute renal failure of intraabdominal hypertensia by patients with septic shock

Research in which 127 patients by septic shock (SS) have been included is made prispective. The Research objective: to reveal frequency and the causes ot development of a syndrome of sharp damage of nephroses (ARFS) at the yielded bunch of patients. All patients have been divided on two bunches depending on size intraabdominal hypertensia (IAH) which level was fixed in 6 hours from the beginning of early purposeful therapy. In the first bunch are included 47 (37 %) patients at whom level IAH exceeded 20 (18; 35) mm hg the Second bunch have formed 80 (63 %) patients with level IAH 17 (8,5; 19) mm hg the First stage ARFS (according to criteria AKIN) has been diagnosed at 40 (85 %) patients of 1 bunch and at 9 (11 %) patients of 2 bunches 0c2 = 63,691; p=0,01). The second stage ARFS at 5 (11 %) patients of 1 bunch and at 67 (84 %) patients of 2 bunches. The analysis of qualitative composition fluid programs has shown that at 85 % of patients of 1 bunch sodium chloride solution, at 71 % of patients of 2 bunches combination XES of 130/0,4 and 0,9 % sodium chloride solution in interrelations 1:1 or 1:2 has been applied. Thus, one of the leading causes of development ARFS at patients septic shock is not IAH, and use in the program of early purposeful therapy of solutions of starch.Проведено проспективное, исследование, в которое было включено 127 пациентов септическим шоком (СШ). Цель исследования: выявить частоту и причины развития синдрома острого повреждения почек (СОПП) у данной группы больных. Все пациенты были разделены на две группы в зависимости от величины интраабдоминальной гипертензии (ИАГ). уровень которой фиксировался через 6 часов от начало ранней целенаправленной терапии. В первую группу включены 47(37%) пациентов, у которых уровень ИАГ превышал 20 (18; 35) мм рт. ст. Вторую группу образовали 80 (63%) больных с уровнем ИАГ 17 (8,5; 19) мм рт. ст. Первая стадия СОПП (согласно критериям AKIN) была диагностирована у 40 (85%) пациентов 1 группы и у 9 (11%) больных 2 группы (/2 = 63,691; р=0,01). Вторая стадия СОПП у 5(11%) пациентов 1 группы и у 67 (84%) больных 2 группы. Анализ качественного состава инфузионной программы показал, что у 85% пациентов 1 группы был применен 0,9% раствор хлористого натрия, у 71% больных 2 группы сочетание ГЗК 130/0,4 и 0,9% раствор хлористого натрия в соотношениях 1:1 или 1:2. Таким образом, одной из ведущих причин развития СОПП у пациентов септическим шоком является не ИАГ, а использование в программе ранней целенаправленной терапии растворов крахмала

A computational group theoretic symmetry reduction package for the SPIN model checker

Symmetry reduced model checking is hindered by two problems: how to identify state space symmetry when systems are not fully symmetric, and how to determine equivalence of states during search. We present TopSpin, a fully automatic symmetry reduction package for the Spin model checker. TopSpin uses the Gap computational algebra system to effectively detect state space symmetry from the associated Promela specification, and to choose an efficient symmetry reduction strategy by classifying automorphism groups as a disjoint/wreath product of subgroups. We present encouraging experimental results for a variety of Promela examples

The Importance of Connexin 43 in Enamel Development and Mineralization

During enamel development, formation of hydroxyapatite crystals and regulation of pH in the enamel matrix require massive transport of ions. Both ameloblasts and adjacent dental epithelial cells in the stellate reticulum co-express several transmembrane cotransporters/ion-exchangers for transport of ions across plasma membranes. Gap junctions (GJs) enable intercellular exchanges of ions between neighboring cells. This suggests that the ameloblasts and other cell layers of the enamel organ, form a functional unit. During the bell stage of tooth formation, the non-ameloblast dental epithelium highly expresses the Na-K-Cl cotransporter (Nkcc1). Nkcc1-null mice are associated with enamel hypomineralization and increased expression of GJ protein connexin 43 (Cx43), suggesting that reduced ion transport in the Nkcc1-null mouse is in part compensated by increased intercellular ion transport through GJs. To understand the role of GJs in ion transport and its effect on pH regulation, we examined in a mouse strain in which Cx43 was ablated selectively in DMP1 expressing cells (Cx43flox/flox mice crossed with DMP1-8kb-Cre mice), including ameloblasts. Micro-CT analysis showed that the mineral density at late maturation stage incisal enamel of the Cx43-null mice was 10% less than in controls, whereas that in dentin was unchanged. Maturation stage ameloblasts of mice lacking the pH regulating sodium/bicarbonate transporter NBCe1 (Nbce1-null), or chloride channel Cftr (Cftr-null) were found to have increased Cx43-immunostaining. These results support the possibility that GJs in the ameloblast–papillary complex at the maturation stage contribute to ion transport by enabling passage of ions directly from cells of the papillary layer into ameloblast layer. Increasing the number of GJs may partly compensate the reduction of ion-cotransporters and ion exchangers in dental epithelium

Magnet Laboratory Research

Contains reports on five research projects.United States Atomic Energy Commission (Contract AT(30-1)-1283