Mechanisms underlying bone loss associated with gut inflammation

Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted gut immune response. Gastrointestinal disease is recognized as an immune malfunction driven by multiple factors, including cytokines and signaling molecules. However, the mechanism by which intestinal inflammation magnified by gut-residing actors stimulates bone loss remains to be elucidated. In this article, we discuss the main risk factors potentially contributing to intestinal disease-associated bone loss, and summarize current animal models, illustrating gut-bone axis to bridge the gap between intestinal inflammation and skeletal disease

Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies

Total joint replacement, although considered an excellent surgical procedure, can be complicated by osteolysis induced by implant particles and subsequent aseptic loosening of the implant. The pathogenesis of implant-associated osteolysis includes inflammatory and osteolytic processes. The sustained chronic inflammatory response initiated by particulate debris at the implant-bone interface is manifested by recruitment of a wide array of cell types. These cells include macrophages, fibroblasts, giant cells, neutrophils, lymphocytes, and – most importantly – osteoclasts, which are the principal bone resorbing cells. The 'cellular response' entails secretion of osteoclastogenic and inflammatory cytokines that favor exacerbated osteoclast activity and enhanced osteolysis. An appreciation of the complex network that leads to these cellular and inflammatory responses will form a foundation on which to develop therapeutic interventions to combat inflammatory periprosthetic bone loss

An Integrated Collaboration Framework for Sustainable Sugar Supply Chains

Stakeholders in sugar supply chains face challenges to identify strengths and weaknesses, as well as opportunities and capabilities of all collaborating stakeholders. This paper proposes a conceptual model as a framework for sustainable sugar supply chains to achieve an effective collaboration system. This model identifies essential elements and how they are linked in the boundary of sustainability. An existing general collaboration model is selected as the basis to develop a new supply chain collaboration model based on the characteristics, the synergies, and the elements. The framework consisting of six elements: boundary and context; drivers (value proposition, assets, and supply chain capabilities); stakeholder requirements; collaboration system requirements; quality indicators; and a common goal. This conceptual model gives insight to the sugar stakeholders who join in collaboration regarding what are the specific drivers and elements that possible and essential to propose a sustainable collaboration, what their roles are, and how they are linked. The finding can be used as the basis for a collaboration quality assessment model

Experimental study of foaming agents in water and their application in the metal foaming.

In this study an experimental investigation was performed on foaming process of water-alcoholic mixtures. The aim of this study is to provide an illustration on foaming phenomena in water alcoholic-mixtures, and an investigation of its application in foaming process in molten metal. In the first and second sections of this study a comprehensive review was presented on physiochemical properties and theory of foaming process in both water-alcoholic mixtures and molten metal. In the third and fourth parts a description of the experimental setup and procedures were presented with results. In the last section a conclusion of results was presented. The used experiment has three main parts: in the first part best foaming conditions were specified by air injection in water-ethanol and water-isopropanol mixtures at different alcoholic volume fractions from 0 to 1 at 50 L/h flow rate and 20 seconds foaming time. While in the second part foaming behavior analyzed at different flow rate (15, 25, 50 and 75 L/h) and foaming time (20, 35, 55 seconds). In the third part, drainage velocity was calculated by using a proposed method based on literature data. Furthermore, an Image processing code was written to analyze experimental data. According to previous measured data, the dimensionless parameters: Reynolds, Marangoni, and Capillary numbers were calculated. The result of this study shows that, for water-isopropyl mixtures foam did not appear, while for water-ethanol mixtures a best foaming condition occurred at 0.15 ethanol volume fraction. Also, the drainage velocity was mainly a function of foam thickness.In this study an experimental investigation was performed on foaming process of water-alcoholic mixtures. The aim of this study is to provide an illustration on foaming phenomena in water alcoholic-mixtures, and an investigation of its application in foaming process in molten metal. In the first and second sections of this study a comprehensive review was presented on physiochemical properties and theory of foaming process in both water-alcoholic mixtures and molten metal. In the third and fourth parts a description of the experimental setup and procedures were presented with results. In the last section a conclusion of results was presented. The used experiment has three main parts: in the first part best foaming conditions were specified by air injection in water-ethanol and water-isopropanol mixtures at different alcoholic volume fractions from 0 to 1 at 50 L/h flow rate and 20 seconds foaming time. While in the second part foaming behavior analyzed at different flow rate (15, 25, 50 and 75 L/h) and foaming time (20, 35, 55 seconds). In the third part, drainage velocity was calculated by using a proposed method based on literature data. Furthermore, an Image processing code was written to analyze experimental data. According to previous measured data, the dimensionless parameters: Reynolds, Marangoni, and Capillary numbers were calculated. The result of this study shows that, for water-isopropyl mixtures foam did not appear, while for water-ethanol mixtures a best foaming condition occurred at 0.15 ethanol volume fraction. Also, the drainage velocity was mainly a function of foam thickness

Constitutive activation of IKK2/NF-κB impairs osteogenesis and skeletal development

Pathologic conditions impair bone homeostasis. The transcription factor NF-κB regulates bone homeostasis and is central to bone pathologies. Whereas contribution of NF-κB to heightened osteoclast activity is well-documented, the mechanisms underlying NF-κB impact on chondrocytes and osteoblasts are scarce. In this study, we examined the effect of constitutively active IKK2 (IKK2ca) on chondrogenic and osteogenic differentiation. We show that retroviral IKK2ca but not GFP, IKK2WT, or the inactive IKK2 forms IKK2KM and IKK2SSAA, strongly suppressed osteogenesis and chondrogenesis, in vitro. In order to explore the effect of constitutive NF-κB activation on bone formation in vivo, we activated this pathway in a conditional fashion. Specifically, we crossed the R26StopIKK2ca mice with mice carrying the Col2-cre in order to express IKK2ca in osteoblasts and chondrocytes. Both chondrocytes and osteoblasts derived from Col2Cre/IKK2ca expressed IKK2ca. Mice were born alive yet died shortly thereafter. Histologically, newborn Col2Cre+/RosaIKK2ca heterozygotes (Cre+IKK2ca_w/f (het)) and homozygotes (Cre+IKK2ca_f/f (KI)) showed smaller skeleton, deformed vertebrate and reduced or missing digit ossification. The width of neural arches, as well as ossification in vertebral bodies of Cre+IKK2ca_w/f and Cre+IKK2ca_f/f, was reduced or diminished. H&E staining of proximal tibia from new born pups revealed that Cre+IKK2ca_f/f displayed disorganized hypertrophic zones within the smaller epiphysis. Micro-CT analysis indicated that 4-wk old Cre+IKK2ca_w/f has abnormal trabecular bone in proximal tibia compared to WT littermates. Mechanistically, ex-vivo experiments showed that expression of differentiation markers in calvarial osteoblasts derived from newborn IKK2ca knock-in mice was diminished compared to WT-derived cells. In situ hybridization studies demonstrated that the hypertrophic chondrocyte marker type-X collagen, the pre-hypertrophic chondrocyte markers Indian hedgehog and alkaline phosphatase, and the early markers Aggrecan and type-II collagen were reduced in Cre+IKK2ca_w/f and Cre+IKK2ca_f/f mice. Altogether, the in-vitro, in vivo and ex-vivo evidence suggest that IKK2ca perturbs osteoblast and chondrocyte maturation and impairs skeletal development

Chronic inflammation triggered by the NLRP3 inflammasome in myeloid cells promotes growth plate dysplasia by mesenchymal cells

AbstractSkeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice. These responses are IL-1 signaling-dependent, but independent of PARP1, which also functions downstream of NLRP3 and regulates skeletal homeostasis. Mechanistically, inflammation causes severe anemia and hypoxia in the bone environment, yet down-regulates the HIF-1α pathway in chondrocytes, thereby promoting the demise of these cells. Thus, activation of NLRP3 in hematopoietic cells initiates IL-1β-driven paracrine cascades, which promote abnormal growth plate development in NOMID mice.</jats:p

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a twofold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKβ nor overexpression of caIKKβ significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration), and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared with female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NFκB and instead may be regulated by autophagy in a sex-specific manner