-
Frontiers in Bioscience (Landmark... Jun 2010G protein signaling is comprised of G protein coupled receptors (GPCRs) that detect ligands or sense cations, heterotrimeric G proteins, and downstream effectors and... (Review)
Review
G protein signaling is comprised of G protein coupled receptors (GPCRs) that detect ligands or sense cations, heterotrimeric G proteins, and downstream effectors and regulators. G protein signaling plays important roles in bone development, remodeling, and disease. In human cases, mutations of certain GPCRs and G proteins impair bone development and metabolism, resulting in bone diseases. This review focuses on the functions of G proteins and GPCRs in osteoblasts and osteoclasts, their signaling pathways, and their gene mutations in mouse models and human diseases. We have discussed the roles of all four types of G proteins (i.e. Gs, Gq/11, Gi/o, and G12/13) and assessed the roles of the GPCRs, such as type 1 Parathyroid hormone receptor (PTH1R), calcitonin receptor, cation sensing receptor (CaSR), relaxin family peptides, cannabinoid receptor, frizzleds, and proton sensing receptor in normal bone formation and remodeling. The roles of regulators of G protein signaling (RGS) and GTPase-activating proteins (GAP) in G-protein signaling pathways are also reviewed. Lastly, we give perspective for the research of G protein signaling in bone development and disease.
Topics: Animals; Bone Development; Bone Diseases; Cell Proliferation; GTP-Binding Proteins; Humans; Osteoblasts; Osteoclasts; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 20515736
DOI: 10.2741/3656 -
Gene Mar 2011The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in... (Review)
Review
The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hdacs in bone development and biology have been elucidated though in vitro and in vivo models. Recent findings suggest that clinical usage of small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder, cancer, and a multitude of other ailments may have unintended effects on bone cell populations. Here we review the progress that has been made in the last decade in understanding how Hdacs contribute to bone development and maintenance.
Topics: Animals; Bone Development; Bone and Bones; Gene Expression Regulation, Developmental; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Mice; Osteoblasts; Osteoclasts; Rats; Transcription Factors
PubMed: 21185361
DOI: 10.1016/j.gene.2010.12.003 -
The Journal of Nutrition, Health & Aging 2007Low bone mass (osteoporosis) is a silent epidemic of the 21st century, which presently in the UK results in over 200,000 fractures annually at a cost of over one billion... (Review)
Review
Low bone mass (osteoporosis) is a silent epidemic of the 21st century, which presently in the UK results in over 200,000 fractures annually at a cost of over one billion pounds. Figures are set to increase worldwide. Understanding the factors which affect bone metabolism is thus of primary importance in order to establish preventative measures or treatments for this condition. Nutrition is an important determinant of bone health, but the effects of the individual nutrients and minerals, other than calcium, is little understood. Accumulating evidence over the last 30 years strongly suggest that dietary silicon is beneficial to bone and connective tissue health and we recently reported strong positive associations between dietary Si intake and bone mineral density in US and UK cohorts. The exact biological role(s) of silicon in bone health is still not clear, although a number of possible mechanisms have been suggested, including the synthesis of collagen and/or its stabilization, and matrix mineralization. This review gives an overview of this naturally occurring dietary element, its metabolism and the evidence of its potential role in bone health.
Topics: Aging; Bone Density; Bone Density Conservation Agents; Bone Development; Bone and Bones; Diet; Humans; Osteoporosis; Silicon; Trace Elements
PubMed: 17435952
DOI: No ID Found -
Current Opinion in Genetics &... Oct 1994Recent progress in the study of regulation of bone and cartilage differentiation has come from the isolation, cloning, and expression of genes encoding bone... (Review)
Review
Recent progress in the study of regulation of bone and cartilage differentiation has come from the isolation, cloning, and expression of genes encoding bone morphogenetic proteins (BMPs). BMPs initiate cartilage and bone formation in a sequential cascade. Their pleiotropic effects on chemotaxis, mitosis, and differentiation are based on concentration-dependent thresholds. The existence of multiple members of the BMP family raises issues concerning functional redundancy. Current work in progress in different laboratories has revealed that BMP-2 or BMP-4 gene knockout by homologous recombination results, surprisingly, in embryonic lethality. Cartilage and bone differentiation during endochondral development involves a continuum of steps: initiation, promotion, maintenance, modeling, and termination. The signaling factors for initiation and maintenance are being defined at the molecular level, and future studies will focus on the gene regulation of initial signaling molecules such as BMPs. Critical progress in the determination of the role of BMPs in bone development has been accomplished by systematic study of skeletal mutations such as short ear and brachypodism in mice. The accelerating pace of advance in this area augurs well for the resolution of the molecular basis of morphogenesis of bone and cartilage.
Topics: Animals; Biological Evolution; Bone Development; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Proteins; Cartilage; Extracellular Matrix; Gene Expression Regulation, Developmental; Humans; Molecular Structure; Mutation; Proteins; Receptors, Cell Surface; Receptors, Growth Factor
PubMed: 7849513
DOI: 10.1016/0959-437x(94)90141-o -
Vitamins and Hormones 2018Thyroid hormone (TH) is an established regulator of skeletal growth and maintenance both in clinical studies and in laboratory models. The clinical consequences of... (Review)
Review
Thyroid hormone (TH) is an established regulator of skeletal growth and maintenance both in clinical studies and in laboratory models. The clinical consequences of altered thyroid status on the skeleton during development and in adulthood are well known, and genetic mouse models in which elements of the TH signaling axis have been manipulated illuminate the mechanisms which underlie TH regulation of the skeleton. TH is involved in the regulation of the balance between proliferation and differentiation in several skeletal cell types including chondrocytes, osteoblasts, and osteoclasts. The effects of TH are mediated primarily via the thyroid hormone receptors (TRs) α and β, ligand-inducible nuclear receptors which act as transcription factors to regulate target gene expression. Both TRα and TRβ signaling are important for different stages of skeletal development. The molecular mechanisms of TH action in bone are complex and include interaction with a number of growth factor signaling pathways. This review provides an overview of the regulation and mechanisms of TH action in bone, focusing particularly on the role of TH in endochondral bone formation during postnatal growth.
Topics: Animals; Bone Development; Gene Expression Regulation, Developmental; Humans; Receptors, Thyroid Hormone; Thyroid Hormones
PubMed: 29407442
DOI: 10.1016/bs.vh.2017.06.003 -
Experimental Physiology Feb 2021What is the topic of this review? Mechanisms regulating bone length and skeletal proportions What advances does it highlight? The study of differential bone length... (Review)
Review
NEW FINDINGS
What is the topic of this review? Mechanisms regulating bone length and skeletal proportions What advances does it highlight? The study of differential bone length between leg and finger bones, metatarsals of the Egyptian jerboa and genomic analysis of giraffes.
ABSTRACT
Among mammalian species, skeletal structures vary greatly in size and shape, leading to a dramatic variety of body sizes and proportions. How different bones grow to different lengths, whether among different species, different individuals of the same species, or even in different anatomical parts of our the body, has always been a fascinating subject of research in biology and physiology. In the current review, we focus on some of the recent advances in the field and discuss how these provided important new insights into the mechanisms regulating bone length and skeletal proportions.
Topics: Animals; Body Size; Bone Development; Bone and Bones; Chondrocytes; Growth Plate; Mammals
PubMed: 33369789
DOI: 10.1113/EP089086 -
Bone Research Aug 2023Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an...
Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an integrin-associated focal adhesion protein, from murine limbs causes defects in endochondral ossification and dwarfism. The mutant long bones were shorter but wider, and the growth plates became disorganized, especially in the proliferative zone. With two-photon time-lapse imaging of bone explant culture, we provide direct evidence showing that α-parvin regulates chondrocyte rotation, a process essential for chondrocytes to form columnar structure. Furthermore, loss of α-parvin increased binucleation, elevated cell death, and caused dilation of the resting zones of mature growth plates. Single-cell RNA-seq analyses revealed alterations of transcriptome in all three zones (i.e., resting, proliferative, and hypertrophic zones) of the growth plates. Our results demonstrate a crucial role of α-parvin in long bone development and shed light on the cellular mechanism through which α-parvin regulates the longitudinal growth of long bones.
Topics: Animals; Mice; Bone Development; Cell Death; Chondrocytes; Growth Plate; Osteogenesis
PubMed: 37607905
DOI: 10.1038/s41413-023-00284-7 -
Physiological Reviews Jan 2001Sex steroids are essential for skeletal development and the maintenance of bone health throughout adult life, and estrogen deficiency at menopause is a major... (Review)
Review
Sex steroids are essential for skeletal development and the maintenance of bone health throughout adult life, and estrogen deficiency at menopause is a major pathogenetic factor in the development of osteoporosis in postmenopausal women. The mechanisms by which the skeletal effects of sex steroids are mediated remain incompletely understood, but in recent years there have been considerable advances in our knowledge of how estrogens and, to a lesser extent androgens, influence bone modeling and remodeling in health and disease. New insights into estrogen receptor structure and function, recent discoveries about the development and activity of osteoclasts, and lessons learned from human and animal genetic mutations have all contributed to increased understanding of the skeletal effects of estrogen, both in males and females. Studies of untreated and treated osteoporosis in postmenopausal women have also contributed to this knowledge and have provided unequivocal evidence for the potential of high-dose estrogen therapy to have anabolic skeletal effects. The development of selective estrogen receptor modulators has provided a new approach to the prevention of osteoporosis and other major diseases of menopause and has implications for the therapeutic use of other steroid hormones, including androgens. Further elucidation of the mechanisms by which sex steroids affect bone thus has the potential to improve the clinical management not only of osteoporosis, both in men and women, but also of a number of other diseases related to sex hormone status.
Topics: Androgens; Animals; Bone Density; Bone Development; Bone and Bones; Estrogens; Female; Humans; Male; Osteoporosis; Progesterone; Receptors, Androgen; Receptors, Estrogen; Selective Estrogen Receptor Modulators
PubMed: 11152762
DOI: 10.1152/physrev.2001.81.1.419 -
Transactions of the American Clinical... 2017The hallmark of rheumatoid arthritis is synovitis, or inflammation of synovial tissues lining joints. Synovitis in rheumatoid arthritis promotes destruction of articular... (Review)
Review
The hallmark of rheumatoid arthritis is synovitis, or inflammation of synovial tissues lining joints. Synovitis in rheumatoid arthritis promotes destruction of articular bone by inducing the differentiation and function of osteoclasts, leading to significant patient morbidity. The cell types and pathways mediating articular bone destruction have now been elucidated and the critical role of receptor activator of nuclear factor-kappa B ligand has been recognized, leading to the identification of new targets for the protection of articular bone. Synovitis not only promotes bone destruction, but also inhibits the ability of bone-forming osteoblasts to repair bone. In stark contrast, inflammation in spondyloarthritis, including ankylosing spondylitis, promotes bone formation at periosteal sites, resulting in pain and decreased motion of the spine and joints. Local anatomic factors contribute to these distinct outcomes for bone and anabolic pathways regulating bone formation are now being investigated to identify novel targets for prevention of abnormal bone formation.
Topics: Bone Development; Bone and Bones; Humans; Rheumatic Diseases
PubMed: 28790485
DOI: No ID Found -
Hormone Research in Paediatrics 2021Longitudinal bone growth is regulated by multiple endocrine signals (e.g., growth hormone, insulin-like growth factor I, estrogen, and androgen) and local factors (e.g.,... (Review)
Review
BACKGROUND
Longitudinal bone growth is regulated by multiple endocrine signals (e.g., growth hormone, insulin-like growth factor I, estrogen, and androgen) and local factors (e.g., fibroblast growth factors and their receptors and the C-natriuretic peptide/natriuretic peptide receptor-B pathway).
SUMMARY
Abnormalities in both endocrine and local regulation of growth plate physiology cause many disorders of human skeletal growth. Knowledge of these pathways creates therapeutic potential for sustaining or even augmenting linear growth. Key Message: During the past 4 decades, advances in understanding growth plate physiology have been accompanied by development and implementation of growth-promoting treatments that have progressed in both efficacy and specificity of action. This paper reviews the history and continuing evolution of growth plate therapeutics.
Topics: Bone Development; Estrogens; Fibroblast Growth Factors; Growth Hormone; Growth Plate; Humans
PubMed: 34758467
DOI: 10.1159/000520812