Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of ...the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.
Abstract Bone has the unique capacity to heal without the formation of a fibrous scar, likely because several of the cellular and molecular processes governing bone healing recapitulate the events ...during skeletal development. A critical component in bone healing is the timely appearance of blood vessels in the fracture callus. Angiogenesis, the formation of new blood vessels from pre-existing ones, is stimulated after fracture by the local production of numerous angiogenic growth factors. The fracture vasculature not only supplies oxygen and nutrients, but also stem cells able to differentiate into osteoblasts and in a later phase also the ions necessary for mineralization. This review provides a concise report of the regulation of angiogenesis by bone cells, its importance during bone healing and its possible therapeutic applications in bone tissue engineering. This article is part of a Special Issue entitled “Stem Cells and Bone”.
Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor ...4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.
The development, maintenance of healthy bone and regeneration of injured tissue in the human body comprise a set of intricate and finely coordinated processes. However, an analysis of current bone ...regeneration strategies shows that only a small fraction of well-reported bone biology aspects has been used as inspiration and transposed into the development of therapeutic products. Specific topics that include inter-scale bone structural organization, developmental aspects of bone morphogenesis, bone repair mechanisms, role of specific cells and heterotypic cell contact in the bone niche (including vascularization networks and immune system cells), cell-cell direct and soluble-mediated contact, extracellular matrix composition (with particular focus on the non-soluble fraction of proteins), as well as mechanical aspects of native bone will be the main reviewed topics. In this Review we suggest a systematic parallelization of (i) fundamental well-established biology of bone, (ii) updated and recent advances on the understanding of biological phenomena occurring in native and injured tissue, and (iii) critical discussion of how those individual aspects have been translated into tissue regeneration strategies using biomaterials and other tissue engineering approaches. We aim at presenting a perspective on unexplored aspects of bone physiology and how they could be translated into innovative regeneration-driven concepts.
Bone fragility is a major health concern, as the increased risk of bone fractures has devastating outcomes in terms of mortality, decreased autonomy, and healthcare costs. Efforts made to address ...this problem have considerably increased our knowledge about the mechanisms that regulate bone formation and resorption. In particular, we now have a much better understanding of the cellular events that are triggered when bones are mechanically stimulated and how these events can lead to improvements in bone mass. Despite these findings at the molecular level, most exercise intervention studies reveal either no effects or only minor benefits of exercise programs in improving bone mineral density (BMD) in osteoporotic patients. Nevertheless, and despite that BMD is the gold standard for diagnosing osteoporosis, this measure is only able to provide insights regarding the quantity of bone tissue. In this article, we review the complex structure of bone tissue and highlight the concept that its mechanical strength stems from the interaction of several different features. We revisited the available data showing that bone mineralization degree, hydroxyapatite crystal size and heterogeneity, collagen properties, osteocyte density, trabecular and cortical microarchitecture, as well as whole bone geometry, are determinants of bone strength and that each one of these properties may independently contribute to the increased or decreased risk of fracture, even without meaningful changes in aBMD. Based on these findings, we emphasize that while osteoporosis (almost) always causes bone fragility, bone fragility is not always caused just by osteoporosis, as other important variables also play a major role in this etiology. Furthermore, the results of several studies showing compelling data that physical exercise has the potential to improve bone quality and to decrease fracture risk by influencing each one of these determinants are also reviewed. These findings have meaningful clinical repercussions as they emphasize the fact that, even without leading to improvements in BMD, exercise interventions in patients with osteoporosis may be beneficial by improving other determinants of bone strength.
A virus‐activated matrix is developed to overcome the challenge of forming vascularized bone tissue. It is generated by filling a 3D printed bioceramic scaffold with phage nanofibers displaying ...high‐density RGD peptide. After it is seeded with mesenchymal stem cells (MSCs) and implanted into a bone defect, the phage nanofibers induce osteogenesis and angiogenesis by activating endothelialization and osteogenic differentiation of MSCs.
Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to ...low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause - the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.
ABSTRACT
Chronic kidney disease (CKD) patients may have high rates of bone loss and fractures, but microarchitectural and biochemical mechanisms of bone loss in CKD patients have not been fully ...described. In this longitudinal study of 53 patients with CKD Stages 2 to 5D, we used dual‐energy X‐ray absorptiometry (DXA), high‐resolution peripheral quantitative computed tomography (HRpQCT), and biochemical markers of bone metabolism to elucidate effects of CKD on the skeleton. Median follow‐up was 1.5 years (range 0.9 to 4.3 years); bone changes were annualized and compared with baseline. By DXA, there were significant declines in areal bone mineral density (BMD) of the total hip and ultradistal radius: −1.3% (95% confidence interval CI −2.1 to −0.6) and −2.4% (95% CI −4.0 to −0.9), respectively. By HRpQCT at the distal radius, there were significant declines in cortical area, density, and thickness and increases in porosity: −2.9% (95% CI −3.7 to −2.2), −1.3% (95% CI −1.6 to −0.6), −2.8% (95% CI −3.6 to −1.9), and +4.2% (95% CI 2.0 to 6.4), respectively. Radius trabecular area increased significantly: +0.4% (95% CI 0.2 to 0.6), without significant changes in trabecular density or microarchitecture. Elevated time‐averaged levels of parathyroid hormone (PTH) and bone turnover markers predicted cortical deterioration. Higher levels of serum 25‐hydroxyvitamin D predicted decreases in trabecular network heterogeneity. These data suggest that significant cortical loss occurs with CKD, which is mediated by hyperparathyroidism and elevated turnover. Future investigations are required to determine whether these cortical losses can be attenuated by treatments that reduce PTH levels and remodeling rates.
Fat and bone Reid, Ian R.
Archives of biochemistry and biophysics,
11/2010, Letnik:
503, Številka:
1
Journal Article
Recenzirano
Body weight is a principal determinant of bone density and fracture risk, and adipose tissue mass is a major contributor to this relationship. In contrast, some recent studies have argued that “fat ...mass after adjustment for body weight” actually has a deleterious effect on bone, but these analyses are confounded by the co-linearity between the variables studied, and therefore have produced misleading results. Mechanistically, fat and bone are linked by a multitude of pathways, which ultimately serve the function of providing a skeleton appropriate to the mass of adipose tissue it is carrying. Adiponectin, insulin/amylin/preptin, leptin and adipocytic estrogens are all likely to be involved in this connection. In the clinic, the key issues are that obesity is protective against osteoporosis, but underweight is a major preventable risk factor for fractures.
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Large bone defects resulting from fractures and disease are a medical concern, being often unable to heal spontaneously by the body’s repair mechanisms. Bone tissue engineering (BTE) ...is a promising approach for treating bone defects through providing a template to guide osseous regeneration. 3D scaffolds with microstructure mimicking host bone are necessary in common BTE strategies. Bioactive glasses (BGs) attract researchers’ attention as BTE scaffolds as they are osteoconductive and osteoinductive in certain formulations. In vivo animal models allow understanding and evaluation of materials’ performance in the complex physiological environment, being an inevitable step before clinical trials. The aim of this paper is to review for the first time published research investigating the in vivo osseous regenerative capacity of 3D BG scaffolds in bone defect animal models, to better understand and evaluate the progress and future outlook of the use of such scaffolds in BTE. The literature analysis reveals that the regenerative capacity of BG scaffolds depends on several factors; including BG composition, fabrication method, scaffold microstructure and pore characteristics, in addition to scaffold pretreatment and whether or not the scaffolds are loaded with growth factors. In addition, animal species selected, defect size and implantation time affect the scaffold in vivo behavior and outcomes. The review of the literature also makes clear the difficulty encountered to compare different types of bioactive glass scaffolds in their bone forming ability. Even considering such limitations of the current state-of-the-art, results generated from animal bone defect models provide an essential source of information to guide the design of BG scaffolds in future.
Bioactive glasses are at the centre of increasing research efforts in bone tissue engineering as the number of research groups around the world carrying out research on this type of biomaterials continues to increase. However, there are no previous reviews in literature which specifically cover investigations of the performance of bioactive glass scaffolds in bone defect animal models. This is the topic of the present review, in which we have analysed comprehensively all available literature in the field. The review thus fills a gap in the biomaterials literature providing a broad platform of information for researchers interested in bioactive glasses in general and specifically in the outcomes of in vivo models. Bioactive glass scaffolds of different compositions tested in relevant bone defect models are covered.
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