-
Cold Spring Harbor Perspectives in... Aug 2018Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net... (Review)
Review
Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net loss of bone mass, despite accelerating bone formation by osteoblasts. Intermittent treatment with PTH analogs represents the only Food and Drug Administration (FDA)-approved bone anabolic osteoporosis treatment strategy. Functional PTH receptors are present on cells of the osteoblast lineage, ranging from early skeletal stem cells to matrix-embedded osteocytes. In addition, bone remodeling by osteoclasts liberates latent growth factors present within bone matrix. Here, we will provide an overview of the multiple cellular and molecular mechanisms through which PTH influences bone homeostasis. Notably, net skeletal effects of continuous versus intermittent can differ significantly. Where possible, we will highlight mechanisms through which continuous hyperparathyroidism leads to bone loss, and through which intermittent hyperparathyroidism boosts bone mass. Given the therapeutic usage of intermittent PTH (iPTH) treatment for osteoporosis, particular attention will be paid toward mechanisms underlying the bone anabolic effects of once daily PTH administration.
Topics: Animals; Bone Remodeling; CD8-Positive T-Lymphocytes; Humans; Mice; Models, Biological; Osteoclasts; Osteocytes; Osteoporosis; Parathyroid Hormone
PubMed: 29358318
DOI: 10.1101/cshperspect.a031237 -
Calcified Tissue International Feb 2012Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor... (Review)
Review
Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor is cleaved following ligand binding, resulting in the release and nuclear translocation of the Notch intracellular domain (NICD). NICD induces gene expression by forming a ternary complex with the DNA binding protein CBF1/Rbp-Jk, Suppressor of Hairless, Lag1, and Mastermind-Like (Maml). Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey) are classic Notch targets. Notch canonical signaling plays a central role in skeletal development and bone remodeling by suppressing the differentiation of skeletal cells. The skeletal phenotype of mice misexpressing Hes1 phenocopies partially the effects of Notch misexpression, suggesting that Hey proteins mediate most of the skeletal effects of Notch. Dysregulation of Notch signaling is associated with diseases affecting human skeletal development, such as Alagille syndrome, brachydactyly and spondylocostal dysostosis. Somatic mutations in Notch receptors and ligands are found in tumors of the skeletal system. Overexpression of NOTCH1 is associated with osteosarcoma, and overexpression of NOTCH3 or JAGGED1 in breast cancer cells favors the formation of osteolytic bone metastasis. Activating mutations in NOTCH2 cause Hajdu-Cheney syndrome, which is characterized by skeletal defects and fractures, and JAG1 polymorphisms, are associated with variations in bone mineral density. In conclusion, Notch is a regulator of skeletal development and bone remodeling, and abnormal Notch signaling is associated with developmental and postnatal skeletal disorders.
Topics: Animals; Bone Development; Bone Diseases; Bone Remodeling; Humans; Receptors, Notch; Signal Transduction
PubMed: 22002679
DOI: 10.1007/s00223-011-9541-x -
Biomolecules May 2023Calcitonin gene-related peptide (CGRP) has 37 amino acids. Initially, CGRP had vasodilatory and nociceptive effects. As research progressed, evidence revealed that the... (Review)
Review
Calcitonin gene-related peptide (CGRP) has 37 amino acids. Initially, CGRP had vasodilatory and nociceptive effects. As research progressed, evidence revealed that the peripheral nervous system is closely associated with bone metabolism, osteogenesis, and bone remodeling. Thus, CGRP is the bridge between the nervous system and the skeletal muscle system. CGRP can promote osteogenesis, inhibit bone resorption, promote vascular growth, and regulate the immune microenvironment. The G protein-coupled pathway is vital for its effects, while MAPK, Hippo, NF-κB, and other pathways have signal crosstalk, affecting cell proliferation and differentiation. The current review provides a detailed description of the bone repair effects of CGRP, subjected to several therapeutic studies, such as drug injection, gene editing, and novel bone repair materials.
Topics: Humans; Calcitonin Gene-Related Peptide; Osteogenesis; Bone Resorption; Bone Remodeling; NF-kappa B
PubMed: 37238709
DOI: 10.3390/biom13050838 -
Medicina 2019Hypovitaminosis D, defined by low serum levels of 25(OH)D, is a recognized worldwide public health problem. The most accepted definition considers that deficiency occurs... (Review)
Review
Hypovitaminosis D, defined by low serum levels of 25(OH)D, is a recognized worldwide public health problem. The most accepted definition considers that deficiency occurs with serum levels fall below 12 ng/ml of 25(OH)D. Long term vitamin D deficiency results in decreased bone mineralization, secondary hyperparathyroidism, increased cortical bone loss (pathogenesis of osteoporosis and hip fractures), differentiation and division of various cell types, muscle strength, diabetes type 2, blood pressure, etc. Twin- and family-based studies indicate that genetic factors influence serum 25(OH)D levels. Genetic studies have shown single-nucleotide polymorphisms (SNPs) are linked to low serum 25(OH)D concentrations through changes in the activity of the enzymes of the 1a,25(OH)2D metabolic pathway. Carriers of high genetic risk scores would need a h igher amount of vitamin D supplementation to achieve adequate serum 25(OH)D concentrations. Clinicians would not need to indicate studies to identify patients with vitamin D insufficiency of genetic origin. They should instruct their patients on their own care, to control the intake of vitamin D and the serum 25(OH)D levels until the latter are adequate. Overall, the literature reveals that the consequences of hypovitaminosis D on bone health are observed in old and infrequently in young subjects. A probable explanation for the latter is: if the rate of bone remodeling allows it, bone tissue has endogenous (genetics, hormones) and exogenous determinants (diet, physical activity) that may compensate the variables of bone health. The consequences of vitamin D deficit on bone health, has not been completely uncovered.
Topics: Bone Remodeling; Female; Humans; Male; Parathyroid Hormone; Polymorphism, Single Nucleotide; Vitamin D Deficiency
PubMed: 31284259
DOI: No ID Found -
International Journal of Oral Science Sep 2015Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the... (Review)
Review
Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that microRNAs (miRNAs), known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression, and growing numbers of novel miRNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis, and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of miRNAs in regulating bone remodeling as well as novel applications for miRNAs in biomaterials for therapeutic purposes.
Topics: Animals; Bone Remodeling; Cell Lineage; Humans; MicroRNAs; Osteoblasts; Transcription, Genetic
PubMed: 26208037
DOI: 10.1038/ijos.2015.22 -
Current Osteoporosis Reports Apr 2023The purpose of this review is to summarize recent findings on copy number variations and susceptibility to osteoporosis. (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarize recent findings on copy number variations and susceptibility to osteoporosis.
RECENT FINDINGS
Osteoporosis is highly influenced by genetic factors, including copy number variations (CNVs). The development and accessibility of whole genome sequencing methods has accelerated the study of CNVs and osteoporosis. Recent findings include mutations in novel genes and validation of previously known pathogenic CNVs in monogenic skeletal diseases. Identification of CNVs in genes previously associated with osteoporosis (e.g. RUNX2, COL1A2, and PLS3) has confirmed their importance in bone remodelling. This process has been associated also with the ETV1-DGKB, AGBL2, ATM, and GPR68 genes, identified by comparative genomic hybridisation microarray studies. Importantly, studies in patients with bone pathologies have associated bone disease with the long non-coding RNA LINC01260 and enhancer sequences residing in the HDAC9 gene. Further functional investigation of genetic loci harbouring CNVs associated with skeletal phenotypes will reveal their role as molecular drivers of osteoporosis.
Topics: DNA Copy Number Variations; Humans; Osteoporosis; Bone Remodeling
PubMed: 36795294
DOI: 10.1007/s11914-023-00773-y -
Frontiers in Bioscience (Elite Edition) Jan 2012Bone is a peculiar connective tissue which functionally interacts with many other organs and tissues, including bone marrow, lymphoid tissue, kidney, adipose tissue,... (Review)
Review
Bone is a peculiar connective tissue which functionally interacts with many other organs and tissues, including bone marrow, lymphoid tissue, kidney, adipose tissue, endocrine pancreas, brain and gonads. Bone functions are accomplished by three principal cell types: the osteoblasts, cells of mesenchymal origin having osteogenic functions, the osteoclasts, giant multinucleated cells arising from the monocyte-macrophage line and devoted to resorb bone, and the osteocytes, the latter arising from mature osteoblasts that, once deposited the bone matrix, remain trapped in it, becoming quiescent cells. Osteocytes are known for their role as mechanosensors, however, old and new evidence showed their active contribution to mineral homeostasis. Moreover, the cross-talk between bone cells is crucial, since a correct bone homeostasis relies on a right coupling between osteoblast and osteoclast functions. Any deregulation of this coupling is responsible for bone disease condition, which reflects on other organs with which bone interacts.
Topics: Animals; Bone Remodeling; Bone and Bones; Humans; Osteoblasts; Osteoclasts
PubMed: 22202038
DOI: 10.2741/543 -
BMC Musculoskeletal Disorders Nov 2020Osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, all have one clear common denominator; an altered turnover of bone. However, this... (Review)
Review
Osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, all have one clear common denominator; an altered turnover of bone. However, this may be more complex than a simple change in bone matrix and mineral turnover. While these diseases share a common tissue axis, their manifestations in the area of pathology are highly diverse, ranging from sclerosis to erosion of bone in different regions. The management of these diseases will benefit from a deeper understanding of the local versus systemic effects, the relation to the equilibrium of the bone balance (i.e., bone formation versus bone resorption), and the physiological and pathophysiological phenotypes of the cells involved (e.g., osteoblasts, osteoclasts, osteocytes and chondrocytes). For example, the process of endochondral bone formation in chondrocytes occurs exists during skeletal development and healthy conditions, but also in pathological conditions. This review focuses on the complex molecular and cellular taxonomy of bone in the context of rheumatological diseases that alter bone matrix composition and maintenance, giving rise to different bone turnover phenotypes, and how biomarkers (biochemical markers) can be applied to potentially describe specific bone phenotypic tissue profiles.
Topics: Bone Remodeling; Bone Resorption; Bone and Bones; Humans; Osteoclasts; Phenotype; Rheumatology
PubMed: 33248451
DOI: 10.1186/s12891-020-03804-2 -
Pharmacological Research Sep 2019Osteoporosis and osteopenia impact more than 54 million Americans, resulting in significant morbidity and mortality. Alterations in bone remodeling are the hallmarks for... (Review)
Review
Osteoporosis and osteopenia impact more than 54 million Americans, resulting in significant morbidity and mortality. Alterations in bone remodeling are the hallmarks for osteoporosis, and thus the development of novel treatments that will prevent or treat bone diseases would be clinically significant, and improve the quality of life for these patients. Bone remodeling involves the removal of old bone by osteoclasts and the formation of new bone by osteoblasts. This process is tightly coupled, and is essential for the maintenance of bone strength and integrity. Since the osteoclast is the only cell capable of bone resorption, the development of drugs to treat bone disorders has primarily focused on reducing osteoclast differentiation, maturation, and bone resorption mechanisms, and there are few treatments that actually increase bone formation. Evidence from observational, experimental, and clinical studies demonstrate a positive link between naturally occurring compounds and improved indices of bone health. While many natural extracts and compounds are reported to have beneficial effects on bone, only resveratrol, sulforaphane, specific phenolic acids and anthocyanins, have been shown to both increase bone formation and reduce resorption through their effects on the bone epigenome. Each of these compounds alters specific aspects of the bone epigenome to improve osteoblast differentiation, reduce osteoblast apoptosis, improve bone mineralization, and reduce osteoclast differentiation and function. This review focuses on these specific natural compounds and their epigenetic regulation of bone remodeling.
Topics: Animals; Biological Products; Bone Remodeling; Epigenesis, Genetic; Humans
PubMed: 31315065
DOI: 10.1016/j.phrs.2019.104350 -
Journal of the World Federation of... Aug 2023The purpose of this review is to provide an update on the changes at the cellular and tissue level occurring during orthodontic force application. For the understanding... (Review)
Review
The purpose of this review is to provide an update on the changes at the cellular and tissue level occurring during orthodontic force application. For the understanding of this process, knowledge of the mechanobiology of the periodontal ligament and the alveolar bone are essential. The periodontal ligament and alveolar bone make up a functional unit that undergoes robust changes during orthodontic tooth movement. Complex molecular signaling is responsible for converting mechanical stresses into biochemical events with a net result of bone apposition and/or bone resorption. Despite an improved understanding of mechanical and biochemical signaling mechanisms, it is largely unknown how mechanical stresses regulate the differentiation of stem/progenitor cells into osteoblast and osteoclast lineages. To advance orthodontics, it is crucial to gain a better understanding of osteoblast differentiation from mesenchymal stem/progenitor cells and osteoclastogenesis from the hematopoietic/monocyte lineage.
Topics: Humans; Tooth Movement Techniques; Alveolar Process; Bone Remodeling; Bone Resorption; Biophysics
PubMed: 37349154
DOI: 10.1016/j.ejwf.2023.05.001