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Cellular & Molecular Biology Letters Sep 2022Osteoporotic fractures lead to increased disability and mortality in the elderly population. With the rapid increase in the aging population around the globe, more... (Review)
Review
Osteoporotic fractures lead to increased disability and mortality in the elderly population. With the rapid increase in the aging population around the globe, more effective treatments for osteoporosis and osteoporotic fractures are urgently required. The underlying molecular mechanisms of osteoporosis are believed to be due to the increased activity of osteoclasts, decreased activity of osteoblasts, or both, which leads to an imbalance in the bone remodeling process with accelerated bone resorption and attenuated bone formation. Currently, the available clinical treatments for osteoporosis have mostly focused on factors influencing bone remodeling; however, they have their own limitations and side effects. Recently, cytokine immunotherapy, gene therapy, and stem cell therapy have become new approaches for the treatment of various diseases. This article reviews the latest research on bone remodeling mechanisms, as well as how this underpins current and potential novel treatments for osteoporosis.
Topics: Aged; Bone Remodeling; Bone Resorption; Humans; Osteoclasts; Osteoporosis; Osteoporotic Fractures
PubMed: 36058940
DOI: 10.1186/s11658-022-00371-3 -
Genesis (New York, N.Y. : 2000) Sep 2022Osteoclasts are large multinucleated cells from hematopoietic origin and are responsible for bone resorption. A balance between osteoclastic bone resorption and... (Review)
Review
Osteoclasts are large multinucleated cells from hematopoietic origin and are responsible for bone resorption. A balance between osteoclastic bone resorption and osteoblastic bone formation is critical to maintain bone homeostasis. The alveolar bone, also called the alveolar process, is the part of the jawbone that holds the teeth and supports oral functions. It differs from other skeletal bones in several aspects: its embryonic cellular origin, the form of ossification, and the presence of teeth and periodontal tissues; hence, understanding the unique characteristic of the alveolar bone remodeling is important to maintain oral homeostasis. Excessive osteoclastic bone resorption is one of the prominent features of bone diseases in the jaw such as periodontitis. Therefore, inhibiting osteoclast formation and bone resorptive process has been the target of therapeutic intervention. Understanding the mechanisms of osteoclastic bone resorption is critical for the effective treatment of bone diseases in the jaw. In this review, we discuss basic principles of alveolar bone remodeling with a specific focus on the osteoclastic bone resorptive process and its unique functions in the alveolar bone. Lastly, we provide perspectives on osteoclast-targeted therapies and regenerative approaches associated with bone diseases in the jaw.
Topics: Bone Remodeling; Bone Resorption; Bone and Bones; Humans; Osteoclasts; Osteogenesis
PubMed: 35757898
DOI: 10.1002/dvg.23490 -
Frontiers in Endocrinology 2021Flavonoids are polyphenolic compounds spotted in various fruits, vegetables, barks, tea plants, and stems and many more natural commodities. They have a multitude of... (Review)
Review
Flavonoids are polyphenolic compounds spotted in various fruits, vegetables, barks, tea plants, and stems and many more natural commodities. They have a multitude of applications through their anti-inflammatory, anti-oxidative, anti-carcinogenic properties, along with the ability to assist in the stimulation of bone formation. Bone, a rigid connective body tissue made up of cells embedded in a mineralised matrix is maintained by an assemblage of pathways assisting osteoblastogenesis and osteoclastogenesis. These have a significant impact on a plethora of bone diseases. The homeostasis between osteoblast and osteoclast formation decides the integrity and structure of the bone. The flavonoids discussed here are quercetin, kaempferol, icariin, myricetin, naringin, daidzein, luteolin, genistein, hesperidin, apigenin and several other flavonoids. The effects these flavonoids have on the mitogen activated protein kinase (MAPK), nuclear factor kappa β (NF-kβ), Wnt/β-catenin and bone morphogenetic protein 2/SMAD (BMP2/SMAD) signalling pathways, and apoptotic pathways lead to impacts on bone remodelling. In addition, these polyphenols regulate angiogenesis, decrease the levels of inflammatory cytokines and play a crucial role in scavenging reactive oxygen species (ROS). Considering these important effects of flavonoids, they may be regarded as a promising agent in treating bone-related ailments in the future.
Topics: Animals; Anti-Inflammatory Agents; Bone Diseases; Bone Remodeling; Flavonoids; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Signal Transduction
PubMed: 34887836
DOI: 10.3389/fendo.2021.779638 -
Archives of Biochemistry and Biophysics May 2008The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and... (Review)
Review
The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
Topics: Animals; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Mice; Osteoclasts; Osteogenesis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction
PubMed: 18395508
DOI: 10.1016/j.abb.2008.03.018 -
International Journal of Molecular... Jul 2019Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can... (Review)
Review
Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction-oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O) and hydrogen peroxide (HO), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.
Topics: Animals; Biomarkers; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Molecular Targeted Therapy; Osteoclasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 31336616
DOI: 10.3390/ijms20143576 -
The Angle Orthodontist 1994Basic Multicellular Unit-based bone remodeling can lead to the removal or conservation of bone, but cannot add to it. Decreased mechanical usage (MU) and acute disuse... (Review)
Review
Basic Multicellular Unit-based bone remodeling can lead to the removal or conservation of bone, but cannot add to it. Decreased mechanical usage (MU) and acute disuse result in loss of bone next to marrow; normal and hypervigorous MU result in bone conservation. Bone modeling by resorption and formation drifts can add bone and reshape the trabeculae and cortex to strengthen them but collectively they do not remove bone. Hypervigorous MU turns this modeling on, and its architectural effects then lower typical peak bone strains caused by future loads of the same kind to a threshold range. Decreased and normal MU leave this modeling off. Where typical peak bone strains stay below a 50 microstrain region (the MESr) the largest disuse effects on remodeling occur. Larger strains depress it and make it conserve existing bone. Strains above a 1500 microstrain region (the MESm) tend to turn lamellar bone modeling drifts on. By adding to, reshaping and strengthening bone, those drifts reduce future strains under the same mechanical loads towards that strain region. Strains above a 3000 microstrain region (the MESp) can turn woven bone drifts on to suppress local lamellar drifts but can strengthen bone faster than lamellar drifts can. Such strains also increase bone microdamage and the remodeling that normally repairs it. Those values compare to bone's fracture strain of about 25,000 microstrain.
Topics: Adaptation, Physiological; Biomechanical Phenomena; Bone Remodeling; Bone and Bones; Humans; Stress, Mechanical
PubMed: 8060014
DOI: 10.1043/0003-3219(1994)064<0175:WLABSA>2.0.CO;2 -
Cells Aug 2021Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and... (Review)
Review
Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine.
Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid maturation of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consisting of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal muscle) explains the EPO pleotropic action as a protection factor for several cells, including the multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken together with its clinical use to treat anemias associated with chronic renal failure and other blood disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue de-regeneration disorders.
Topics: Bone Remodeling; Cell Transdifferentiation; Endothelial Cells; Erythropoiesis; Erythropoietin; Humans; Mesenchymal Stem Cells; Multipotent Stem Cells; Receptors, Erythropoietin; Regenerative Medicine
PubMed: 34440909
DOI: 10.3390/cells10082140 -
Annals of the Rheumatic Diseases Sep 2016Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.
OBJECTIVES
Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.
METHODS
3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone.
RESULTS
Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone.
CONCLUSIONS
Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.
Topics: Animals; Anterior Cruciate Ligament; Bone Remodeling; Bone Resorption; Bone and Bones; Cartilage, Articular; Disease Models, Animal; Disease Progression; Male; Mice; Mice, Inbred C57BL; Osteoarthritis; Osteoclasts; Piperidines; Quinazolinones; Random Allocation; Rats; Rats, Inbred Lew; Transforming Growth Factor beta
PubMed: 26470720
DOI: 10.1136/annrheumdis-2015-207923 -
Endocrine Reviews Oct 2018Landmark advances in skeletal biology have arisen mainly from the identification of disease-causing mutations and the advent of rapid and selective gene-targeting... (Review)
Review
Landmark advances in skeletal biology have arisen mainly from the identification of disease-causing mutations and the advent of rapid and selective gene-targeting technologies to phenocopy human disease in mice. Here, we discuss work on newly identified mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, and crosstalk between bone and vital organs as these relate to the therapeutic targeting of the skeleton.
Topics: Animals; Bone Remodeling; Bone and Bones; Homeostasis; Humans
PubMed: 29897433
DOI: 10.1210/er.2018-00050 -
Current Osteoporosis Reports Oct 2017The bone is able to adapt its structure to mechanical signals via the bone remodeling process governed by mechanosensitive osteocytes. With aging, an imbalance in bone... (Review)
Review
PURPOSE OF REVIEW
The bone is able to adapt its structure to mechanical signals via the bone remodeling process governed by mechanosensitive osteocytes. With aging, an imbalance in bone remodeling results in osteoporosis. In this review, we hypothesized that changes in lacunar morphology underlie the decreased bone mechanoresponsiveness to mechanical loading with aging.
RECENT FINDINGS
Several studies have reported considerable variations in the shape of osteocytes and their lacunae with aging. Since osteocytes can sense matrix strain directly via their cell bodies, the variations in osteocyte morphology may cause changes in osteocyte mechanosensitivity. As a consequence, the load-adaptive response of osteocytes may change with aging, even when mechanical loading would remain unchanged. Though extensive quantitative data is lacking, evidence exists that the osteocyte lacunae are becoming smaller and more spherical with aging. Future dedicated studies might reveal whether these changes would affect osteocyte mechanosensation and the subsequent biological response, and whether this is (one of) the pathways involved in age-related bone loss.
Topics: Aging; Bone Remodeling; Humans; Mechanotransduction, Cellular; Osteocytes; Osteoporosis; Stress, Mechanical
PubMed: 28891009
DOI: 10.1007/s11914-017-0402-z