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Cell Communication and Signaling : CCS Jul 2022Osteoporosis is a common skeletal disease with marked bone loss, deterioration of the bone microstructure and bone fragility. An abnormal bone remodelling cycle with... (Review)
Review
Osteoporosis is a common skeletal disease with marked bone loss, deterioration of the bone microstructure and bone fragility. An abnormal bone remodelling cycle with relatively increased bone resorption is the crucial pathophysiological mechanism. Bone remodelling is predominantly controlled by osteoblasts and osteoclasts, which are specialized cell types that are regulated by a variety of osteogenic and osteoclastic factors, including cytokines expressed within the bone microenvironment under local or systemic inflammatory conditions. Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the communication between cytokines and kinases by binding downstream gene promotors and is involved in a wide range of biological or pathological processes. Emerging evidence suggests that STAT3 and its network participate in bone remodelling and the development of osteoporosis, and this factor may be a potent target for osteoporosis treatment. This review focuses on the role and molecular mechanism of the STAT3 signalling pathway in osteogenesis, osteoclastogenesis and osteoporosis, particularly the bone-related cytokines that regulate the osteoblastic differentiation of bone marrow stromal cells and the osteoclastic differentiation of bone marrow macrophages by initiating STAT3 signalling. This review also examines the cellular interactions among immune cells, haematopoietic cells and osteoblastic/osteoclastic cells. Video abstract.
Topics: Bone Resorption; Cell Differentiation; Cytokines; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; RANK Ligand; STAT3 Transcription Factor
PubMed: 35879773
DOI: 10.1186/s12964-022-00924-1 -
Nature Communications Jun 2021Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA...
Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA Nron as a critical suppressor of bone resorption. We demonstrate that osteoclastic Nron knockout mice exhibit an osteopenia phenotype with elevated bone resorption activity. Conversely, osteoclastic Nron transgenic mice exhibit lower bone resorption and higher bone mass. Furthermore, the pharmacological overexpression of Nron inhibits bone resorption, while caused apparent side effects in mice. To minimize the side effects, we further identify a functional motif of Nron. The delivery of Nron functional motif to osteoclasts effectively reverses bone loss without obvious side effects. Mechanistically, the functional motif of Nron interacts with E3 ubiquitin ligase CUL4B to regulate ERα stability. These results indicate that Nron is a key bone resorption suppressor, and the lncRNA functional motif could potentially be utilized to treat diseases with less risk of side effects.
Topics: Animals; Bone Diseases, Metabolic; Bone Resorption; Cullin Proteins; Estrogen Receptor alpha; Female; Femur; Injections, Intravenous; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Osteoclasts; Osteoporosis; RNA, Long Noncoding; Ubiquitination; Up-Regulation; X-Ray Microtomography
PubMed: 34083547
DOI: 10.1038/s41467-021-23642-7 -
Bone Research Oct 2023Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor... (Review)
Review
Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor dimerization under physiological and pathological conditions. Certain glycans are ligands for lectins, which are carbohydrate-specific receptors. Bone is a complex tissue that provides mechanical support for muscles and joints, and the regulation of bone mass in mammals is governed by complex interplay between bone-forming cells, called osteoblasts, and bone-resorbing cells, called osteoclasts. Bone erosion occurs when bone resorption notably exceeds bone formation. Osteoclasts may be activated during cancer, leading to a range of symptoms, including bone pain, fracture, and spinal cord compression. Our understanding of the role of protein glycosylation in cells and tissues involved in osteoclastogenesis suggests that glycosylation-based treatments can be used in the management of diseases. The aims of this review are to clarify the process of bone resorption and investigate the signaling pathways mediated by glycosylation and their roles in osteoclast biology. Moreover, we aim to outline how the lessons learned about these approaches are paving the way for future glycobiology-focused therapeutics.
Topics: Animals; Humans; Osteoclasts; Glycomics; Bone Resorption; Carrier Proteins; Cell Differentiation; Polysaccharides; Mammals
PubMed: 37884496
DOI: 10.1038/s41413-023-00293-6 -
Biomolecules Dec 2020Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune... (Review)
Review
Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.
Topics: Arthritis, Rheumatoid; Autoantibodies; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Inflammation; Osteoblasts; Osteoclasts; Synovial Membrane
PubMed: 33396412
DOI: 10.3390/biom11010048 -
International Journal of Molecular... Dec 2020This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of... (Review)
Review
This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of the proinflammatory cytokine families and release of factors stored in bone during resorption. The juxtaposition of the catabolic and anabolic resorption-dependent pathways raises new questions about control of release of factors from bone, quantity of release in a variety of conditions, and relation of factors released from bone. The catabolic responses involve release of calcium from bone into the circulation resulting in increased inflammatory response in intensity and/or duration. The release of transforming growth factor beta (TGF-β) from bone suppresses phosphorylation of the AKT/mTOR pathway and stimulates ubiquitin-mediated breakdown of muscle protein. In contrast, muscle IL-6 production is stimulated by undercarboxylated osteocalcin, which signals osteoblasts to produce more RANK ligand, stimulating resorptive release of undercarboxylated osteocalcin, which in turn stimulates muscle fiber nutrient uptake and an increase in muscle mass.
Topics: Animals; Bone Resorption; Humans; Muscular Atrophy
PubMed: 33396572
DOI: 10.3390/ijms22010392 -
Gene Mar 2021Maintenance of optimal bone mass is controlled through the concerted functions of several cell types, including bone resorbing osteoclasts. Osteoclasts function to... (Review)
Review
Maintenance of optimal bone mass is controlled through the concerted functions of several cell types, including bone resorbing osteoclasts. Osteoclasts function to remove calcified tissue during developmental bone modeling, and degrade bone at sites of damage during bone remodeling. Changes to bone homeostasis can arise with alterations in osteoclastogenesis and/or catabolic activity that are not offset by anabolic activity; thus, factors that regulate osteoclastogenesis and bone resorption are of interest to further our understanding of basic bone biology, and as potential targets for therapeutic intervention. Several key cytokines, including RANKL and M-CSF, as well as co-stimulatory factors elicit kinase signaling cascades that promote osteoclastogenesis. These kinase cascades are offset by the action of protein phosphatases, including members of the serine/threonine phosphatase family. Here we review the functions of serine/threonine phosphatases and their control of osteoclast differentiation and function, while highlighting deficiencies in our understanding of this understudied class of proteins within the field.
Topics: Animals; Bone Resorption; Homeostasis; Humans; Macrophage Colony-Stimulating Factor; Osteoclasts; Osteogenesis; Phosphorylation; Protein Serine-Threonine Kinases; RANK Ligand
PubMed: 33338510
DOI: 10.1016/j.gene.2020.145362 -
Biomedicine & Pharmacotherapy =... Nov 2022Osteoporosis is a common bone metabolic disease in postmenopausal women, diabetic patients and obese patients and is characterized by an imbalance in bone formation and... (Review)
Review
Osteoporosis is a common bone metabolic disease in postmenopausal women, diabetic patients and obese patients and is characterized by an imbalance in bone formation and resorption. Current studies have conducted in-depth research on these groups and revealed their respective pathogenesis and treatment measures. However, the causes of osteoporosis in patients are complex, usually combining multiple factors. Unifying the same pathway that induces bone loss in various pathological states will greatly facilitate the diagnosis and treatment of osteoporosis. Purine metabolism is an important biological process in determining genetic orientation and functional performance. Adequate evidence confirms the widespread existence of purine metabolism disorders in various types of osteoporosis. Purine metabolism plays an important role in the process of bone remodeling. The aim of the present study was to determine changes in purine metabolism in high-risk populations with various types of osteoporosis and the pathogenesis of bone loss caused by abnormal purine metabolism. Two states of balance are maintained in the process of bone remodeling including osteogenesis and adipogenesis and osteoblasts and osteoclasts. Abnormal purine metabolism induces hyperuricemia and the accumulation of reactive oxygen species (ROS). Monosodium urate (MSU), ROS and ROS-induced inflammation inhibit the expression of osteogenic turnover indicators and promote osteoclast differentiation. ADA, ADCY, ENPP1 and PDE are the genes involved in purine metabolism most strongly associated with bone remodeling. Constructing a network between purine metabolism and bone metabolism and mining the core regulatory mechanism will contribute to revealing the pathogenesis and optimizing the treatment of osteoporosis.
Topics: Humans; Female; Bone Resorption; Reactive Oxygen Species; Uric Acid; Osteoclasts; Osteoporosis
PubMed: 36271563
DOI: 10.1016/j.biopha.2022.113784 -
Osteoporosis International : a Journal... Dec 2019Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity... (Review)
Review
Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.
Topics: Age Factors; Androstenes; Bone Density; Bone Development; Bone Remodeling; Bone Resorption; Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Estradiol; Estrogens; Female; Humans; Progestins
PubMed: 31446440
DOI: 10.1007/s00198-019-05103-6 -
Cell Mar 2021In this issue of Cell, McDonald et al. show that giant multinucleated, bone-resorbing osteoclasts dissolve into smaller cells, termed "osteopmorhs," which re-form into...
In this issue of Cell, McDonald et al. show that giant multinucleated, bone-resorbing osteoclasts dissolve into smaller cells, termed "osteopmorhs," which re-form into osteoclasts at distal bone sites (McDonald et al., 2021). These findings overturn the long-standing premise that osteoclasts differentiate solely from hematopoietic precursors and undergo apoptosis after completing resorption.
Topics: Bone Resorption; Bone and Bones; Humans; Osteoclasts
PubMed: 33636131
DOI: 10.1016/j.cell.2021.02.023 -
Journal of Molecular Endocrinology Oct 2019FSH has a primary function in procreation, wherein it induces estrogen production in females and regulates spermatogenesis in males. However, in line with our... (Review)
Review
FSH has a primary function in procreation, wherein it induces estrogen production in females and regulates spermatogenesis in males. However, in line with our discoveries over the past decade of non-unitary functions of pituitary hormones, we and others have described hitherto uncharacterized functions of FSH. Through high-affinity receptors, some of which are variants of the ovarian FSH receptor (FSHR), FSH regulates bone mass, adipose tissue function, energy metabolism, and cholesterol production in both sexes. These newly described actions of FSH may indeed be relevant to the pathogenesis of bone loss, dysregulated energy homeostasis, and disordered lipid metabolism that accompany the menopause in females and aging in both genders. We are therefore excited about the possibility of modulating circulating FSH levels toward a therapeutic benefit for a host of age-associated diseases, including osteoporosis, obesity and dyslipidemia, among other future possibilities.
Topics: Animals; Antibodies, Blocking; Bone Resorption; Cholesterol; Follicle Stimulating Hormone; Humans; Menopause; Thermogenesis
PubMed: 31454787
DOI: 10.1530/JME-19-0152