Ultra-processed foods have known negative implications for health; however, their effect on skeletal development has never been explored. Here, we show that young rats fed ultra-processed food rich in fat and sugar suffer from growth retardation due to lesions in their tibial growth plates. The bone mineral density decreases significantly, and the structural parameters of the bone deteriorate, presenting a sieve-like appearance in the cortices and poor trabecular parameters in long bones and vertebrae. This results in inferior mechanical performance of the entire bone with a high fracture risk. RNA sequence analysis of the growth plates demonstrated an imbalance in extracellular matrix formation and degradation and impairment of proliferation, differentiation and mineralization processes. Our findings highlight, for the first time, the severe impact of consuming ultra-processed foods on the growing skeleton. This pathology extends far beyond that explained by the known metabolic effects, highlighting bone as a new target for studies of modern diets.

Current treatments for cartilage lesions are often associated with fibrocartilage formation and donor site morbidity. Mechanical and biochemical stimuli play an important role in hyaline cartilage formation. Biocompatible scaffolds capable of transducing mechanical loads and delivering bioactive instructive factors may better support cartilage regeneration. In this study we aimed to test the interplay between mechanical and FGF-18 mediated biochemical signals on the proliferation and differentiation of primary bovine articular chondrocytes embedded in a chondro-conductive Fibrin-Hyaluronan (FB/HA) based hydrogel. Chondrocytes seeded in a Fibrin-HA hydrogel, with or without a chondro-inductive, FGFR3 selective FGF18 variant (FGF-18v) were loaded into a joint-mimicking bioreactor applying controlled, multi-axial movements, simulating the natural movements of articular joints. Samples were evaluated for DNA content, sulphated glycosaminoglycan (sGAG) accumulation, key chondrogenic gene expression markers and histology. Under moderate loading, samples produced particularly significant amounts of sGAG/DNA compared to unloaded controls. Interestingly there was no significant effect of FGF-18v on cartilage gene expression at rest. Following moderate multi-axial loading, FGF-18v upregulated the expression of Aggrecan (ACAN), Cartilage Oligomeric Matrix Protein (COMP), type II collagen (COL2) and Lubricin (PRG4). Moreover, the combination of load and FGF-18v, significantly downregulated Matrix Metalloproteinase-9 (MMP-9) and Matrix Metaloproteinase-13 (MMP-13), two of the most important factors contributing to joint destruction in OA. Biomimetic mechanical signals and FGF-18 may work in concert to support hyaline cartilage regeneration and repair. Statement of significance Articular cartilage has very limited repair potential and focal cartilage lesions constitute a challenge for current standard clinical procedures. The aim of the present research was to explore novel procedures and constructs, based on biomaterials and biomechanical algorithms that can better mimic joints mechanical and biochemical stimulation to promote regeneration of damaged cartilage. Using a hydrogel-based platform for chondrocyte 3D culture revealed a synergy between mechanical forces and growth factors. Exploring the mechanisms underlying this mechano-biochemical interplay may enhance our understanding of cartilage remodeling and the development of new strategies for cartilage repair and regeneration. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Neural crest cells (NCCs) are a unique embryonic cell population that initially reside at the dorsal neural tube but later migrate in the embryo and differentiate into multiple types of derivatives. To acquire motility, NCCs undergo epithelial-to-mesenchymal transition and invade the surrounding extracellular matrix (ECM). Matrix metalloproteases (MMPs) are a large family of proteases which regulate migration of various embryonic and adult cells via ECM remodeling. The gelatinase's subgroup of MMPs is the most studied one due to its key role in metastasis. As it is composed of only two proteases, MMP2 and MMP9, it is important to understand whether each is indispensable or redundant in its biological function. Here we explored the role of the gelatinases in executing NCC migration, by determining whether MMP2 and/or MMP9 regulate migration across species in singular, combined, or redundant manners. Chick and mouse embryos were utilized to compare expression and activity of both MMPs using genetic and pharmacological approaches in multiple in vivo and ex vivo assays. Both MMPs were found to be expressed and active in mouse and chick NCCs. Inhibition of each MMP was sufficient to prevent NCC migration in both species. Yet, NCC migration was maintained in MMP2(-/-) or MMP9(-/-) mouse mutants due to compensation between the gelatinases, but reciprocal pharmacological inhibition in each mutant prevented NCC migration. This study reveals for the first time that both gelatinases are expressed in avian and mammalian NCCs, and demonstrates their fundamental and conserved role in promoting embryonic cell migration.

N-3 polyunsaturated fatty acids (PUFAs) are essential nutrients that must be obtained from the diet. We have previously showed that endogenous n-3 PUFAs contribute to skeletal development and bone quality in fat-1 mice. Unlike other mammals, these transgenic mice, carry the n-3 desaturase gene and thus can convert n-6 to n-3 PUFAs endogenously. Since this model does not mimic dietary exposure to n-3 PUFAs, diets rich in fish and flaxseed oils were used to further elucidate the role of n-3 PUFAs in bone development. Our investigation reveals that dietary n-3 PUFAs decrease fat accumulation in the liver, lower serum fat levels, and alter fatty acid (FA) content in liver and serum. Bone analyses show that n-3 PUFAs improve mechanical properties, which were measured using a three-point bending test, but exert complex effects on bone structure that vary according to its source. In a micro-CT analysis, we found that the flaxseed oil diet improves trabecular bone micro-architecture, whereas the fish oil diet promotes higher bone mineral density (BMD) with no effect on trabecular bone. The transcriptome characterization of bone by RNA-seq identified regulatory mechanisms of n-3 PUFAs via modulation of the cell cycle and peripheral circadian rhythm genes. These results extend our knowledge and provide insights into the molecular mechanisms of bone remodeling regulation induced by different sources of dietary n-3 PUFAs.

Obesity has been traditionally viewed as a protective factor for fractures. Recent studies have challenged this concept, particularly regarding abdominal obesity. We aimed to investigate the association between abdominal obesity, body mass index (BMI) and fragility fractures prevalence in a sample of community-dwelling elderly Israeli women.

Current treatments for cartilage lesions are often associated with fibrocartilage formation and donor site morbidity. Mechanical and biochemical stimuli play an important role in hyaline cartilage formation. Biocompatible scaffolds capable of transducing mechanical loads and delivering bioactive instructive factors may better support cartilage regeneration. In this study we aimed to test the interplay between mechanical and FGF-18 mediated biochemical signals on the proliferation and differentiation of primary bovine articular chondrocytes embedded in a chondro-conductive Fibrin-Hyaluronan (FB/HA) based hydrogel. Chondrocytes seeded in a Fibrin-HA hydrogel, with or without a chondro-inductive, FGFR3 selective FGF18 variant (FGF-18v) were loaded into a joint-mimicking bioreactor applying controlled, multi-axial movements, simulating the natural movements of articular joints. Samples were evaluated for DNA content, sulphated glycosaminoglycan (sGAG) accumulation, key chondrogenic gene expression markers and histology. Under moderate loading, samples produced particularly significant amounts of sGAG/DNA compared to unloaded controls. Interestingly there was no significant effect of FGF-18v on cartilage gene expression at rest. Following moderate multi-axial loading, FGF-18v upregulated the expression of Aggrecan (ACAN), Cartilage Oligomeric Matrix Protein (COMP), type II collagen (COL2) and Lubricin (PRG4). Moreover, the combination of load and FGF-18v, significantly downregulated Matrix Metalloproteinase-9 (MMP-9) and Matrix Metaloproteinase-13 (MMP-13), two of the most important factors contributing to joint destruction in OA. Biomimetic mechanical signals and FGF-18 may work in concert to support hyaline cartilage regeneration and repair.Statement of significance Articular cartilage has very limited repair potential and focal cartilage lesions constitute a challenge for current standard clinical procedures. The aim of the present research was to explore novel procedures and constructs, based on biomaterials and biomechanical algorithms that can better mimic joints mechanical and biochemical stimulation to promote regeneration of damaged cartilage. Using a hydrogel-based platform for chondrocyte 3D culture revealed a synergy between mechanical forces and growth factors. Exploring the mechanisms underlying this mechano-biochemical interplay may enhance our understanding of cartilage remodeling and the development of new strategies for cartilage repair and regeneration.

Abstract Neural crest cells (NCCs) are a unique embryonic cell population that initially reside at the dorsal neural tube but later migrate in the embryo and differentiate into multiple types of derivatives. To acquire motility, NCCs undergo epithelial-to-mesenchymal transition and invade the surrounding extracellular matrix (ECM). Matrix metalloproteases (MMPs) are a large family of proteases which regulate migration of various embryonic and adult cells via ECM remodeling. The gelatinase's subgroup of MMPs is the most studied one due to its key role in metastasis. As it is composed of only two proteases, MMP2 and MMP9, it is important to understand whether each is indispensable or redundant in its biological function. Here we explored the role of the gelatinases in executing NCC migration, by determining whether MMP2 and/or MMP9 regulate migration across species in singular, combined, or redundant manners. Chick and mouse embryos were utilized to compare expression and activity of both MMPs using genetic and pharmacological approaches in multiple in vivo and ex vivo assays. Both MMPs were found to be expressed and active in mouse and chick NCCs. Inhibition of each MMP was sufficient to prevent NCC migration in both species. Yet, NCC migration was maintained in MMP2?/? or MMP9?/? mouse mutants due to compensation between the gelatinases, but reciprocal pharmacological inhibition in each mutant prevented NCC migration. This study reveals for the first time that both gelatinases are expressed in avian and mammalian NCCs, and demonstrates their fundamental and conserved role in promoting embryonic cell migration.

BackgroundGrowth impairment was previously described in milk-allergic children but was not examined in adults on reaching final height.BackgroundGrowth impairment was previously described in milk-allergic children but was not examined in adults on reaching final height.

Background: Obesity has been traditionally viewed as a protective factor for fractures. Recent studies have challenged this concept, particularly regarding abdominal obesity. We aimed to investigate the association between abdominal obesity, body mass index (BMI) and fragility fractures prevalence in a sample of community-dwelling elderly Israeli women. Methods: The data in this cross-sectional study were based on ‘Mabat Zahav’—a survey of a nationally representative sample of elderly Israelis. The study population included 669 women. Data on fragility fractures site and circumstances were self-reported, and height, weight, waist and calf circumferences were measured. Waist circumference (WC) variable was divided into tertiles: < 88 cm, 88–99 cm and > 99 cm. Results: Sixty-five women reported fragility fractures (14 hip fractures, 18 vertebral fractures and 39 wrist fractures). Mean age was 73.9 ± 5.9 years, mean BMI was 29.9 ± 5 kg/m2 and mean WC was 93.9 ± 12 cm. While BMI was not associated with osteoporotic fractures, abdominal obesity (WC > 88 cm) was positively associated with fragility fractures, independently of age, smoking, physical activity [middle and high WC tertiles 3.15 (95% CI 1.41–7.02), 2.78 (95% CI 1.05–7.31), respectively]. Conclusions: Among this sample of elderly women, abdominal obesity was positively associated with fragility fractures, independently of age, smoking, physical activity and BMI. Waist circumference, an easily measured anthropometric indicator, may be useful for assessing the risk of fragility fractures in elderly women, particularly among those with normal or high BMI—a vast population which has been traditionally considered as having lower fracture risk. © 2019, Springer Nature Switzerland AG.

Bone’s ability to change its morphology in response to load is widely attributed to osteocytes. A study of fish shows that bone can respond to load even in the absence of osteocytes, using a molecular mechanism that is conserved across vertebrates, albeit with different cellular effectors.

BackgroundGrowth impairment was previously described in milk-allergic children but was not examined in adults on reaching final height. Objectives To investigate the dietary intake and final stature of young adults with IgE-mediated cow's milk allergy (IgE-CMA) as compared with nonallergic controls. Methods Eighty-seven patients with IgE-CMA, median age 19.5 years (interquartile range [IQR], 17.3-22.7), and 36 control participants without food allergies, median age 22.7 years (IQR, 18.9-26.1), were studied. Anthropometric and nutritional data were collected. Age and gender z-scores were determined according to the Centers for Disease Control and Prevention growth charts. Nutrient intake assessment was based on dietary records. Individuals with conditions or treatments affecting bone metabolism or growth, other than asthma, were excluded. Results Mean values of height z-scores were significantly reduced in CMA subjects compared with controls (−0.64 ± 0.9 vs −0.04 ± 0.7, P = .001). In contrast, no differences were found between the 2 groups in weight and body mass index z-scores. Patients with CMA had significantly lower intake of protein, and several essential vitamins (A, B12, and riboflavin) and minerals (calcium, potassium, phosphorus, magnesium, and zinc) compared with controls (P < .05), but the intakes of calories, carbohydrate, and fat were not significantly different between the 2 groups. Differences between actual and expected (based on midparental height) height z-scores were comparable in CMA subjects with or without asthma and between those with and without additional food allergies. Conclusions Young adults who have CMA from infancy are at risk of not reaching their growth potential. Growth and nutritional monitoring and appropriate dietary intervention are of particular importance in these at-risk individuals.

The structural, compositional and mechanical properties of the spines of the dorsal fin in mature anosteocytic blue tilapia Oreochromis aureus and osteocytic common carp Cyprinus carpio are described, as well as their temporal growth pattern and regenerative capacities. The three-dimensional architecture of both spines, from macro to sub-micron levels, is shown to be axially oriented and therefore highly anisotropic and the spines of both species are able to regenerate after partial amputation.

Neural crest cells (NCCs) are a transient population of neuroectodermal-originated cells that populate the dorsal neural tube (dNT), before migrating and giving rise to multiple cell lineages in the developing embryo. Prior to their migration, NCCs undergo epithelial-to-mesenchymal-transition (EMT) through which they lose cell contacts and detach from the dNT to invade their surrounding environment. Multiple signals and transcription factors have been identified to regulate these events. Yet, less is known regarding effectors that act downstream to execute the actual NCC separation and migration. Matrix metalloproteinases (MMPs) are a family of proteases that degrade the extracellular matrix as well as other pericellular proteins during processes of tissue remodeling, angiogenesis and metastasis. Previously, we and others have demonstrated the role of the gelatinases MMP2 and MMP9 during the onset of NCC migration. Several evidences link the cleavage and activation of these secreted gelatinases to the activity of membrane-type MMPs (MT-MMP), such as MMP14 and MMP16, which are tethered to plasma membrane and affect various cellular behaviors. The aim of this study was to investigate whether MMP16 acts in NCCs. Here we demonstrate the expression of MMP16 mRNA and protein in cranial NCCs in avian embryos. Knockdown of MMP16 inhibited NCC migration. This inhibition was rescued by the addition of recombinant MMP16, which was also sufficient to increase proper NCC migration. Furthermore, excess MMP16 caused enhanced NCC EMT, concomitant with degradation of dNT-related proteins, laminin and N-cadherin. Altogether, these results uncover MMP16 as a new effector participating in EMT and in the migration of NCCs.

Neural crest cells (NCCs) are transient cell populations that are initially residing at the dorsal-most part of the neural tube of the developing vertebrate embryo. At well-defined time points, NCCs detach from the neural tube as they undergo epithelial-to-mesenchymal transition (EMT) and migrate in distinct pathways to their final destinations. There, this unique cell population differentiates into a great variety of cell types including bone and cartilage tissues of the head and face, connective tissue of the heart, skin melanocytes, adipocytes, enteric neurons, and most of the peripheral sensory neurons, glia, and Schwann cells. Matrix metalloproteinases (MMPs) are a large family of matrix-degrading enzymes, which are divided into several subfamilies according to their structure and substrate specificity. The gelatinases subfamily, which includes MMP-2 and MMP-9 solely, is the most investigated group. Both MMP-2 and MMP-9 were previously reported to be expressed in embryonic NCCs and to have a role in their EMT and migration processes. In this review we present the most recent data regarding the role of MMP-2 and MMP-9 in embryonic NCCs and in their various derivatives in later embryonic stages and in adults.

Objectives:To evaluate the use of Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) in a primary health care clinic in the community and to assess the impact of its use on medical staff's awareness of nutritional status. Methods: STAMP scoring system was tested as is and with modifications in the ambulatory setting. Nutritional risk according to STAMP was compared with a detailed nutritional assessment performed by a registered dietitian. Recording of nutrition-related data and anthropometric measurements in medical files were compared prior and post implementation. Results: Sixty children were included (31 girls, 52%), ages between 1 and 6 years, mean age 2.8 ± 1.5 (mean ± SD). STAMP scores yielded a fair agreement between STAMP and the dietitian's nutritional assessment: κ = 0.47 (95% confidence interval [CI] 0.24–0.7), sensitivity of 47.62% (95% CI 28.34–67.63). Modified STAMP yielded more substantial agreement: κ = 0.57 (95% CI 0.35–0.79), sensitivity of 76.19% (95% CI 54.91–89.37), specificity of 82.05% (95% CI 67.33–91.02). The use of STAMP resulted in an increase in recording of appetite, dietary intake, and anthropometric measurements. Conclusions: Modification of the STAMP improved nutritional risk evaluation in community setting. The use of STAMP in a primary health care clinic raised clinician's awareness to nutritional status. Further work will identify whether this could be translated into lower malnutrition rates and better child care.

Sharks, rays and other elasmobranch fishes are characterized by a skeletal type that is unique among living vertebrates, comprised predominantly of an unmineralized cartilage, covered by a thin outer layer of sub-millimeter, mineralized tiles called tesserae. The mineralized portion of the skeleton appears to grow only by apposition, adding material at the edges of each tessera; maintenance of non-mineralized joints between tesserae is therefore vital, with precise control of mineral deposition and inhibition at the many thousands of growth fronts in the skeleton. Yet, we have only scattered evidence as to how the elasmobranchs mineralize and grow their skeletons. In this review, we take an “environment to skeleton” approach, drawing together research from a vast range of perspectives to track calcium and phosphate from the typical elasmobranch habitats into and through the body, to their deposition at tesseral growth fronts. In the process, we discuss the available evidence for skeletal resorption capability, mineral homeostasis hormones, and nucleation inhibition mechanisms. We also outline relevant theories in crystal nucleation and typical errors in measurements of serum calcium and phosphate in the study of vertebrate biology. We assemble research that suggests consensus in some concepts in elasmobranch skeletal development, but also highlight the very large gaps in our knowledge, particularly in regards to endocrine functional networks and biomineralization mechanisms. In this way, we lay out frameworks for future directions in the study of elasmobranch skeletal biology with stronger and more comparative links to research in other disciplines and into other taxa.