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Nature Sep 2023Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct...
Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct biology of vertebral bone has so far remained unknown. Here we identify a vertebral skeletal stem cell (vSSC) that co-expresses ZIC1 and PAX1 together with additional cell surface markers. vSSCs display formal evidence of stemness, including self-renewal, label retention and sitting at the apex of their differentiation hierarchy. vSSCs are physiologic mediators of vertebral bone formation, as genetic blockade of the ability of vSSCs to generate osteoblasts results in defects in the vertebral neural arch and body. Human counterparts of vSSCs can be identified in vertebral endplate specimens and display a conserved differentiation hierarchy and stemness features. Multiple lines of evidence indicate that vSSCs contribute to the high rates of vertebral metastatic tropism observed in breast cancer, owing in part to increased secretion of the novel metastatic trophic factor MFGE8. Together, our results indicate that vSSCs are distinct from other skeletal stem cells and mediate the unique physiology and pathology of vertebrae, including contributing to the high rate of vertebral metastasis.
Topics: Humans; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Self Renewal; Neoplasm Metastasis; Osteoblasts; Spine; Stem Cells; Biomarkers
PubMed: 37704733
DOI: 10.1038/s41586-023-06519-1 -
Cell Metabolism May 2024Bone secretory proteins, termed osteokines, regulate bone metabolism and whole-body homeostasis. However, fundamental questions as to what the bona fide osteokines and...
Bone secretory proteins, termed osteokines, regulate bone metabolism and whole-body homeostasis. However, fundamental questions as to what the bona fide osteokines and their cellular sources are and how they are regulated remain unclear. In this study, we analyzed bone and extraskeletal tissues, osteoblast (OB) conditioned media, bone marrow supernatant (BMS), and serum, for basal osteokines and those responsive to aging and mechanical loading/unloading. We identified 375 candidate osteokines and their changes in response to aging and mechanical dynamics by integrating data from RNA-seq, scRNA-seq, and proteomic approaches. Furthermore, we analyzed their cellular sources in the bone and inter-organ communication facilitated by them (bone-brain, liver, and aorta). Notably, we discovered that senescent OBs secrete fatty-acid-binding protein 3 to propagate senescence toward vascular smooth muscle cells (VSMCs). Taken together, we identified previously unknown candidate osteokines and established a dynamic regulatory network among them, thus providing valuable resources to further investigate their systemic roles.
Topics: Animals; Osteoblasts; Mice; Bone and Bones; Proteomics; Mice, Inbred C57BL; Male; Aging; Humans; Cellular Senescence; Muscle, Smooth, Vascular; Multiomics
PubMed: 38574738
DOI: 10.1016/j.cmet.2024.03.006 -
Science Translational Medicine Aug 2023Sulfation is a widespread modification of biomolecules that has been incompletely explored to date. Through cross-phenotype meta-analysis of bone mineral density in up... (Meta-Analysis)
Meta-Analysis
Sulfation is a widespread modification of biomolecules that has been incompletely explored to date. Through cross-phenotype meta-analysis of bone mineral density in up to 426,824 genotyped human participants along with phenotypic characterization of multiple mutant mouse lines, we identified a causative role for sulfate transporter solute carrier family 26 member A2 () deficiency in osteoporosis. Ablation of in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited peculiar pericellular matrix (PCM) production characterized by undersulfation coupled with decreased stiffness. These altered chemophysical properties of the PCM disrupted the formation of focal adhesions in osteoblasts. Bulk RNA sequencing and functional assays revealed that the mechanoreciprocal inhibition of focal adhesion kinase (FAK) and Yes1-associated transcriptional regulator (YAP)/WW domain containing transcription regulator 1 (TAZ) signaling impinged osteoblast maturation upon deficiency. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running ameliorated -deficient osteoporosis by promoting YAP/TAZ activity. Analysis of mouse single-cell RNA sequencing data suggested coordination among sulfate metabolism, focal adhesion, and YAP/TAZ activity during osteoblast-to-osteocyte transition. In addition to the -deficient setting, altered FAK and YAP/TAZ signaling was also observed in bone cells of ovariectomized mice and patients with osteoporosis, and pharmacological enforcing of YAP/TAZ activity ameliorated bone loss in ovariectomized mice. Collectively, these data unveil a role for sulfation in the developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.
Topics: Humans; Animals; Mice; Bone Diseases, Metabolic; Osteoblasts; Osteoporosis; Bone Density; Biological Assay; Intracellular Signaling Peptides and Proteins
PubMed: 37611084
DOI: 10.1126/scitranslmed.adg3983 -
Journal of Bone and Mineral Research :... Aug 2023miR-196b-5p plays a role in various malignancies. We have recently reported its function in regulating adipogenesis. However, it remains to be clarified whether and how...
miR-196b-5p plays a role in various malignancies. We have recently reported its function in regulating adipogenesis. However, it remains to be clarified whether and how miR-196b-5p affects bone cells and bone homeostasis. In this study, in vitro functional experiments showed an inhibitory effect of miR-196b-5p on osteoblast differentiation. Mechanistic explorations revealed that miR-196b-5p directly targeted semaphorin 3a (Sema3a) and inhibited Wnt/β-catenin signaling. SEMA3A attenuated the impaired osteogenesis induced by miR-196b-5p. Osteoblast-specific miR-196b transgenic mice showed significant reduction of bone mass. Trabecular osteoblasts were reduced and bone formation was suppressed, whereas osteoclasts, marrow adipocytes, and serum levels of bone resorption markers were increased in the transgenic mice. The osteoblastic progenitor cells from the transgenic mice had decreased SEMA3A levels and exhibited retarded osteogenic differentiation, whereas those marrow osteoclastic progenitors exhibited enhanced osteoclastogenic differentiation. miR-196b-5p and SEMA3A oppositely regulated the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin. The calvarial osteoblastic cells expressing the transgene promoted osteoclastogenesis, whereas the osteoblasts overexpressing Sema3a inhibited it. Finally, in vivo transfection of miR-196b-5p inhibitor to the marrow reduced ovariectomy-induced bone loss in mice. Our study has identified that miR-196b-5p plays a key role in osteoblast and osteoclast differentiation and regulates bone homeostasis. Inhibition of miR-196b-5p may be beneficial for amelioration of osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Female; Mice; Cell Differentiation; Homeostasis; Mice, Transgenic; MicroRNAs; Osteoblasts; Osteoclasts; Osteogenesis; Semaphorin-3A
PubMed: 37221130
DOI: 10.1002/jbmr.4834 -
Biomedicine & Pharmacotherapy =... Dec 2023Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a... (Review)
Review
Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a role in cell differentiation, proliferation, apoptosis, redox balance, amino acid uptake, and glycolipid metabolism. ATF4 induces the differentiation of bone marrow mesenchymal stem cells (BM-MSCs) into osteoblasts, increases osteoblast activity, and inhibits osteoclast formation, promoting bone formation and remodeling. In addition, ATF4 mediates the energy metabolism in osteoblasts and promotes angiogenesis. ATF4 is also involved in the mediation of adipogenesis. ATF4 can selectively accumulate in osteoblasts. ATF4 can directly interact with RUNT-related transcription factor 2 (RUNX2) and up-regulate the expression of osteocalcin (OCN) and osterix (Osx). Several upstream factors, such as Wnt/β-catenin and BMP2/Smad signaling pathways, have been involved in ATF4-mediated osteoblast differentiation. ATF4 promotes osteoclastogenesis by mediating the receptor activator of nuclear factor κ-B (NF-κB) ligand (RANKL) signaling. Several agents, such as parathyroid (PTH), melatonin, and natural compounds, have been reported to regulate ATF4 expression and mediate bone metabolism. In this review, we comprehensively discuss the biological activities of ATF4 in maintaining bone homeostasis and inhibiting OP development. ATF4 has become a therapeutic target for OP treatment.
Topics: Humans; Activating Transcription Factor 4; Osteoclasts; Cell Differentiation; Signal Transduction; Osteoblasts; Osteogenesis; Osteoporosis
PubMed: 37948991
DOI: 10.1016/j.biopha.2023.115864 -
Current Osteoporosis Reports Dec 2023Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone.... (Review)
Review
PURPOSE OF REVIEW
Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone. Since osteocytes are significant in mechanotransduction and orchestrate osteoclast and osteoblast activity, they likely play a central role in orthodontic tooth movement. In this review, we attempt to shed light on the impact and role of osteocyte mechanotransduction during orthodontic tooth movement.
RECENT FINDINGS
Mechanically loaded osteocytes produce signaling molecules, e.g., bone morphogenetic proteins, Wnts, prostaglandins, osteopontin, nitric oxide, sclerostin, and RANKL, which modulate the recruitment, differentiation, and activity of osteoblasts and osteoclasts. The major signaling pathways activated by mechanical loading in osteocytes are the wingless-related integration site (Wnt)/β-catenin and RANKL pathways, which are key regulators of bone metabolism. Moreover, osteocytes are capable of orchestrating bone adaptation during orthodontic tooth movement. A better understanding of the role of osteocyte mechanotransduction is crucial to advance orthodontic treatment. The optimal force level on the periodontal tissues for orthodontic tooth movement producing an adequate biological response, is debated. This review emphasizes that both mechanoresponses and inflammation are essential for achieving tooth movement clinically. To fully comprehend the role of osteocyte mechanotransduction in orthodontic tooth movement, more knowledge is needed of the biological pathways involved. This will contribute to optimization of orthodontic treatment and enhance patient outcomes.
Topics: Humans; Osteocytes; Mechanotransduction, Cellular; Tooth Movement Techniques; Osteoclasts; Osteoblasts; Bone Remodeling
PubMed: 37792246
DOI: 10.1007/s11914-023-00826-2 -
International Journal of Molecular... Dec 2023The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal.... (Review)
Review
The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis.
Topics: Adult; Humans; Osteoblasts; Osteoclasts; Bone Diseases; Osteogenesis; Arthritis, Rheumatoid; Bone Resorption
PubMed: 38203403
DOI: 10.3390/ijms25010233 -
Frontiers in Endocrinology 2023Bone is a dynamic organ that, once formed, undergoes a constant remodeling process that includes bone resorption and synthesis. Osteoclasts and osteoblasts are primarily... (Review)
Review
Bone is a dynamic organ that, once formed, undergoes a constant remodeling process that includes bone resorption and synthesis. Osteoclasts and osteoblasts are primarily responsible for controlling this process. X-box binding protein 1 (XBP1), a transcription factor, affects the metabolism of bones in various ways. In recent years, numerous studies have revealed that XBP1 plays a vital role in bone metabolism, including osteoclast and osteoblast development, as well as in regulating immune cell differentiation that affects the immune microenvironment of bone remodeling. In this review, we highlight the regulatory mechanisms of XBP1 on osteoclasts and osteoblasts, how XBP1 affects the immune microenvironment of bone remodeling by influencing the differentiation of immune cells, and predict the possible future research directions of XBP1 to provide new insights for the treatment of bone-related metabolic diseases.
Topics: Humans; X-Box Binding Protein 1; Osteoclasts; Osteoblasts; Bone Resorption; Bone and Bones
PubMed: 37795354
DOI: 10.3389/fendo.2023.1217579 -
The Journal of International Medical... Aug 2023Sclerostin, a protein encoded by the sclerostin () gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van... (Review)
Review
Sclerostin, a protein encoded by the sclerostin () gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van Buchem's disease, and craniodiaphyseal dysplasia, sclerostin has been identified as an important regulator of bone homeostasis, controlling bone formation by osteoblasts through inhibition of the canonical Wnt signaling pathway. Recent studies have highlighted a hypothetical role of sclerostin in myogenesis, thus modulating the interaction between bone and muscle. This narrative review provides an overview of the clinical implications of sclerostin modulation on skeletal muscle mass and function, and bone metabolism. Improving knowledge about muscle-bone crosstalk may represent a turning point in the development of therapeutic strategies for musculoskeletal disorders, particularly osteosarcopenia.
Topics: Humans; Hyperostosis; Knowledge; Muscles; Osteoblasts; Osteogenesis
PubMed: 37632438
DOI: 10.1177/03000605231193293 -
International Journal of Molecular... Apr 2024Adult bones are continuously remodeled by the balance between bone resorption by osteoclasts and subsequent bone formation by osteoblasts. Many studies have provided... (Review)
Review
Adult bones are continuously remodeled by the balance between bone resorption by osteoclasts and subsequent bone formation by osteoblasts. Many studies have provided molecular evidence that bone remodeling is under the control of circadian rhythms. Circadian fluctuations have been reported in the serum and urine levels of bone turnover markers, such as digested collagen fragments and bone alkaline phosphatase. Additionally, the expressions of over a quarter of all transcripts in bones show circadian rhythmicity, including the genes encoding master transcription factors for osteoblastogenesis and osteoclastogenesis, osteogenic cytokines, and signaling pathway proteins. Serum levels of calcium, phosphate, parathyroid hormone, and calcitonin also display circadian rhythmicity. Finally, osteoblast- and osteoclast-specific knockout mice targeting the core circadian regulator gene show disrupted bone remodeling, although the results have not always been consistent. Despite these studies, however, establishing a direct link between circadian rhythms and bone remodeling in vivo remains a major challenge. It is nearly impossible to repeatedly collect bone materials from human subjects while following circadian changes. In addition, the differences in circadian gene regulation between diurnal humans and nocturnal mice, the main model organism, remain unclear. Filling the knowledge gap in the circadian regulation of bone remodeling could reveal novel regulatory mechanisms underlying many bone disorders including osteoporosis, genetic diseases, and fracture healing. This is also an important question for the basic understanding of how cell differentiation progresses under the influence of cyclically fluctuating environments.
Topics: Bone Remodeling; Animals; Circadian Rhythm; Humans; Osteoblasts; Osteogenesis; Osteoclasts; Gene Expression Regulation; Bone and Bones
PubMed: 38731934
DOI: 10.3390/ijms25094717