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Current Osteoporosis Reports Jun 2021Bone matrix exhibits great complexity in its composition, structure and mechanics. Here, we provide a review of recent research articles and appraise the evidence that... (Review)
Review
PURPOSE OF REVIEW
Bone matrix exhibits great complexity in its composition, structure and mechanics. Here, we provide a review of recent research articles and appraise the evidence that bone matrix quality is clinically important and possibly targetable for fracture prevention.
RECENT FINDINGS
Deformation of mineralised collagen fibrils determines bone fracture mechanics. Slipping and separation at the mineral-fibril and fibril-fibril interfaces, respectively, are the structural mechanisms for plastic deformation and microcrack nucleation. Existing technologies for assessing bone tissue in vivo cannot measure matrix structure or fracture mechanics but have shown limited use in clinical settings for identifying fragility or following treatment outcomes based on composition. Matrix is biomechanically and clinically important, but the knowledge has not translated into clinical practice. The structural mechanisms by which a load is transferred from mineralised collagen fibrils to the whole bone via microcracking have been proven too complex to measure in vivo. The mineral-fibril or fibril-fibril interfaces might be suitable targets for diagnosing fragility or delivering molecules that reduce fracture risk by strengthening the mineral bonds while maintaining flexibility in the fibrils.
Topics: Biomechanical Phenomena; Bone Matrix; Collagen; Elastic Modulus; Fractures, Bone; Humans; Stress, Mechanical
PubMed: 33876386
DOI: 10.1007/s11914-021-00678-8 -
Journal of Bone and Mineral Research :... Aug 2023The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone...
The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ-free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice. We tested this hypothesis using adult (20- to 21-week-old) C57BL/6J GF and conventionally raised female and male mice (n = 6-10/group). Trabecular microarchitecture and cortical geometry were measured from micro-CT of the femur distal metaphysis and cortical midshaft. Whole-femur strength and estimated material properties were measured using three-point bending and notched fracture toughness. Bone matrix properties were measured for the cortical femur by quantitative back-scattered electron imaging and nanoindentation, and, for the humerus, by Raman spectroscopy and fluorescent advanced glycation end product (fAGE) assay. Shifts in cortical tissue metabolism were measured from the contralateral humerus. GF mice had reduced bone resorption, increased trabecular bone microarchitecture, increased tissue strength and decreased whole-bone strength that was not explained by differences in bone size, increased tissue mineralization and fAGEs, and altered collagen structure that did not decrease fracture toughness. We observed several sex differences in GF mice, most notably for bone tissue metabolism. Male GF mice had a greater signature of amino acid metabolism, and female GF mice had a greater signature of lipid metabolism, exceeding the metabolic sex differences of the conventional mice. Together, these data demonstrate that the GF state in C57BL/6J mice alters bone mass and matrix properties but does not decrease bone fracture resistance. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Female; Male; Mice; Animals; Mice, Inbred C57BL; Bone and Bones; Bone Density; Bone Matrix; Fractures, Bone
PubMed: 37221143
DOI: 10.1002/jbmr.4835 -
Current Osteoporosis Reports Jun 2012Bone mineral density alone cannot reliably predict fracture risk in humans and laboratory animals. Therefore, other factors including the quality of organic bone matrix... (Review)
Review
Bone mineral density alone cannot reliably predict fracture risk in humans and laboratory animals. Therefore, other factors including the quality of organic bone matrix components and their interactions may be of crucial importance to understanding of fragility fractures. Emerging research evidence shows, that in addition to collagen, certain noncollagenous proteins (NCPs) play a significant role in the structural organization of bone and influence its mechanical properties. However, their contribution to bone strength still remains largely undefined. Collagen and NCPs undergo different post-translational modifications, which alter the quality of the extracellular matrix and the response of bone to mechanical load. The primary focus of this overview is on NCPs that, together with collagen, contribute to structural and mechanical properties of bone. Current information on several mechanisms through which some NCPs influence bone's resistance to fracture, including the role of nonenzymatic glycation, is also presented.
Topics: Animals; Biomechanical Phenomena; Bone Density; Bone Matrix; Collagen; Fractures, Bone; Humans; Models, Animal; Osteoporosis; Risk Factors
PubMed: 22535528
DOI: 10.1007/s11914-012-0103-6 -
Bone Dec 2021Osteocytes are dynamic, bone matrix-remodeling cells that form an intricate network of interconnected projections through the bone matrix, called the lacunar-canalicular... (Review)
Review
Osteocytes are dynamic, bone matrix-remodeling cells that form an intricate network of interconnected projections through the bone matrix, called the lacunar-canalicular system. Osteocytes are the dominant mechanosensory cells in bone and their mechanosensory and mechanotransductive functions follow their morphological form. During osteocytogenesis and development of the osteocyte lacunar-canalicular network, osteocytes must dramatically remodel both their cytoskeleton and their extracellular matrix. In this review, we summarize our current understanding of the mechanisms that govern osteocyte differentiation, cytoskeletal morphogenesis, mechanotransduction, and matrix remodeling. We postulate that the physiologic activation of matrix remodeling in adult osteocytes, known as perilacunar/canalicular remodeling (PLR) represents a re-activation of the developmental program by which the osteocyte network is first established. While much of osteocyte biology remains unclear, new tools and approaches make the present moment a particularly fruitful and exciting time to study the development of these remarkable cells.
Topics: Bone Matrix; Bone Remodeling; Mechanotransduction, Cellular; Morphogenesis; Osteocytes
PubMed: 34245936
DOI: 10.1016/j.bone.2021.116104 -
Current Drug Targets 2017Bone is one of the most common and most dangerous sites for metastatic growth across cancer types, and bone metastasis remains incurable. Unfortunately, the processes by... (Review)
Review
Bone is one of the most common and most dangerous sites for metastatic growth across cancer types, and bone metastasis remains incurable. Unfortunately, the processes by which cancers preferentially metastasize to bone are still not well understood. In this review, we summarize the morphological features, physical properties, and cell signaling events that make bone a unique site for metastasis and bone remodeling. The signaling crosstalk between the tumor cells and bone cells begins a vicious cycle - a self-sustaining feedback loop between the tumor cells and the bone microenvironment composed of osteoclasts, osteoblasts, other bone marrow cells, bone matrix, and vasculature to support both tumor growth and bone destruction. Through this crosstalk, bone provides a fertile microenvironment that can harbor dormant tumor cells, sometimes for long periods, and support their growth by releasing cytokines as the bone matrix is destroyed, similar to providing nutrients for a seed to germinate in soil. However, few models exist to study the late stages of bone colonization by metastatic tumor cells. We describe some of the current methodologies used to study bone metastasis, highlighting the limitations of these methods and alternative future strategies to be used to study bone metastasis. While <i>in vivo</i> animal and patient studies may provide the gold standard for studying metastasis, <i>ex vivo</i> models can be used as an alternative to enable more controlled experiments designed to study the late stages of bone metastasis.
Topics: Animals; Bone Matrix; Bone Neoplasms; Bone and Bones; Cytokines; Feedback, Physiological; Female; Humans; Male; Models, Biological; Signal Transduction
PubMed: 28025941
DOI: 10.2174/1389450117666161226121650 -
Frontiers in Bioscience (Landmark... Jan 2012Mammalian bones are composed of calcium phosphate crystals in a protein matrix. The major form of the calcium phosphate is hydroxyapatite. The most abundant matrix... (Review)
Review
Mammalian bones are composed of calcium phosphate crystals in a protein matrix. The major form of the calcium phosphate is hydroxyapatite. The most abundant matrix protein in bone is type I collagen. Collagen contributes to the mechanical properties of bone and is necessary for calcification of the tissue. In addition to collagen, several acidic proteins are present as minor components. Osteocalcin is a gamma-carboxyglutamic acid-containing protein of bone, which has an affinity to hydroxyapatite and can prevent crystal growth. Bone sialoprotein (BSP) and osteopontin are acidic glycophosphoproteins of bone. These proteins have RGD cell-attachment sequences and consecutive sequences of acidic amino acids. The poly glutamic acid sequences of BSP act as possible nucleation sites for hydroxyapatite crystals. Dentin phosphoprotein is the major non-collagenous protein of dentin. This protein has (Asp-Ser-Ser) repeat sequences, in which most of the Ser residues are phosphorylated. Some of these acidic matrix proteins are immobilized on the collagen fibrils and induce nucleation of hydroxyapatite crystals. They can also modulate crystal shape by adsorption on a specific face of the crystals.
Topics: Animals; Bone Matrix; Calcification, Physiologic; Proteins
PubMed: 22201843
DOI: 10.2741/4026 -
Tissue Engineering. Part B, Reviews Jun 2017We review the characteristics of osteoblast differentiation and bone matrix synthesis. Bone in air breathing vertebrates is a specialized tissue that developmentally...
We review the characteristics of osteoblast differentiation and bone matrix synthesis. Bone in air breathing vertebrates is a specialized tissue that developmentally replaces simpler solid tissues, usually cartilage. Bone is a living organ bounded by a layer of osteoblasts that, because of transport and compartmentalization requirements, produce bone matrix exclusively as an organized tight epithelium. With matrix growth, osteoblasts are reorganized and incorporated into the matrix as living cells, osteocytes, which communicate with each other and surface epithelium by cell processes within canaliculi in the matrix. The osteoblasts secrete the organic matrix, which are dense collagen layers that alternate parallel and orthogonal to the axis of stress loading. Into this matrix is deposited extremely dense hydroxyapatite-based mineral driven by both active and passive transport and pH control. As the matrix matures, hydroxyapatite microcrystals are organized into a sophisticated composite in the collagen layer by nucleation in the protein lattice. Recent studies on differentiating osteoblast precursors revealed a sophisticated proton export network driving mineralization, a gene expression program organized with the compartmentalization of the osteoblast epithelium that produces the mature bone matrix composite, despite varying serum calcium and phosphate. Key issues not well defined include how new osteoblasts are incorporated in the epithelial layer, replacing those incorporated in the accumulating matrix. Development of bone in vitro is the subject of numerous projects using various matrices and mesenchymal stem cell-derived preparations in bioreactors. These preparations reflect the structure of bone to variable extents, and include cells at many different stages of differentiation. Major challenges are production of bone matrix approaching the in vivo density and support for trabecular bone formation. In vitro differentiation is limited by the organization and density of osteoblasts and by endogenous and exogenous inhibitors.
Topics: Animals; Bone Matrix; Bone Morphogenetic Proteins; Cell Differentiation; Osteoblasts; Osteogenesis
PubMed: 27846781
DOI: 10.1089/ten.TEB.2016.0454 -
Injury Jun 2021In fracture surgery, large bone defects and non-unions often require bone transplantation, and alternatives to autograft bone substitutes in the form of allografts from... (Review)
Review
In fracture surgery, large bone defects and non-unions often require bone transplantation, and alternatives to autograft bone substitutes in the form of allografts from bone banks and the derivate demineralised bone matrix (DBM) are widely used. With a focus on efficacy, clinical evidence, safety, cost, and patient acceptance, this review evaluated the difference between allogeneic allograft or DBM as a bone substitute in trauma surgery. The efficacy in supporting bone healing from allograft and DBM is highly influenced by donor characteristics and graft processing. Mechanical stability is achieved from a structural graft. Based on the existing literature it is difficult to identify where DBM is useful in trauma surgery, and the level of evidence for the relevant use of allograft bone in trauma is low. The risk of transmitting diseases is negligible, and the lowest risk is from DBM due to the extensive processing procedures. A cost comparison showed that DBM is significantly more expensive. The experiences of dental patients have shown that many patients do not want to receive allografts as a bone substitute. It is not possible to definitively conclude whether it makes a difference if allograft or DBM is used in trauma surgery. It is ultimately the surgeon's individual choice, but this article may be useful in providing considerations before a decision is made.
Topics: Allografts; Bone Matrix; Bone Substitutes; Bone Transplantation; Humans; Transplantation, Homologous
PubMed: 33189329
DOI: 10.1016/j.injury.2020.11.013 -
Journal of Bone and Mineral Research :... Dec 1993The bone, dentin, and cementum of the mature individual are comprised from a dense collagenous fiber network into which the carbonate-apatite mineral phase is deposited.... (Review)
Review
The bone, dentin, and cementum of the mature individual are comprised from a dense collagenous fiber network into which the carbonate-apatite mineral phase is deposited. It is hypothesized that a set of collagen-interactive acidic phosphoproteins are secreted by the osteoblasts, odontoblasts, and cementoblasts into the preformed collagenous matrix. These proteins then interact specifically with the collagen and nucleate apatite formation on and within the fibrils. These phosphoproteins may also regulate the morphology, rate of growth, and stability of the mineral phase crystals. The acidic matrix phosphoproteins may thus be considered as the crucial regulators of mineralization and tissue stability. In the dentin system, these regulatory proteins are synthesized, posttranslationally modified, and secreted in vesicles different from the collagen secretory vesicles. Mineralization occurs as the regulatory proteins are deposited on the preformed fibrils. This model requires testing in the bone system. In dentin, in the absence of tissue turnover, the resident phosphoproteins are degraded in situ over time, perhaps changing the properties of the tissue. Regulation of synthesis, secretory pathways and retention of integrity within the matrix are thus important areas for further investigation.
Topics: Amino Acid Sequence; Bone Matrix; Bone and Bones; Calcification, Physiologic; Calcium; Collagen; Dental Cementum; Dentin; Humans; Molecular Sequence Data; Phosphoproteins; Tooth Calcification
PubMed: 8122518
DOI: 10.1002/jbmr.5650081312 -
Journal of Bone and Mineral Research :... Dec 1993The organic matrix of bone contains several protein families, including collagens, proteoglycans, and glycoproteins, all of which may be extensively modified by... (Review)
Review
The organic matrix of bone contains several protein families, including collagens, proteoglycans, and glycoproteins, all of which may be extensively modified by posttranslational events, such as phosphorylation and sulfation. Many of the glycoproteins contain Arg-Gly-Asp (RGD), the integrin-binding sequence, within their structure, whereas other constituent proteins contain gamma-carboxyglutamic acid. The deposition of bone matrix by cells in the osteoblastic lineage is regulated by extrinsic factors, such as systemic and local growth factors and physical forces, and factors that are intrinsic to the cell, such as position in the cell cycle, maturational stage, and developmental age of the donor. Recent studies of several bone matrix gene promoters have identified cis- and trans-acting elements that are responsible for gene activity, although the precise sequence of regulatory events is not known. Development of in vitro assays, coupled with studies of the appearance of these proteins during development in vivo, provides insight into the functions of these proteins during the various stages of bone metabolism. Potential roles for these proteins include proliferation and maturation of stem cells, formation of matrix scaffolding elaborated by bone-forming cells, modeling, and remodeling. Changes in the functional properties of the extracellular matrix may be involved in a variety of disease processes, including osteoporosis and oral bone loss.
Topics: Bone Matrix; Collagen; Extracellular Matrix Proteins; Gene Expression Regulation; Glycoproteins; Humans; Oligopeptides; Osteoporosis; Phosphorylation; Protein Biosynthesis; Proteoglycans; Stereoisomerism
PubMed: 8122516
DOI: 10.1002/jbmr.5650081310