-
Physiological Reviews Jan 2022Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are... (Review)
Review
Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells capable of integrating hormonal and mechanical signals and transmitting them to effector cells in bone and in distant tissues. Osteocytes are a major source of molecules that regulate bone homeostasis by integrating both mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in both rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of several disorders affecting the skeleton. Advances in osteocyte biology initiated the development of novel therapeutics interfering with osteocyte-secreted molecules. Moreover, osteocytes are targets and key distributors of biological signals mediating the beneficial effects of several bone therapeutics used in the clinic. Here we review the most recent discoveries in osteocyte biology demonstrating that osteocytes regulate bone homeostasis and bone marrow fat via paracrine signaling, influence body composition and energy metabolism via endocrine signaling, and contribute to the damaging effects of diabetes mellitus and hematologic and metastatic cancers in the skeleton.
Topics: Animals; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Osteoclasts; Osteocytes; Osteogenesis
PubMed: 34337974
DOI: 10.1152/physrev.00043.2020 -
Seminars in Cell & Developmental Biology Mar 2022Postmenopausal osteoporosis is a systemic disease characterized by the loss of bone mass and increased bone fracture risk largely resulting from significantly reduced... (Review)
Review
Postmenopausal osteoporosis is a systemic disease characterized by the loss of bone mass and increased bone fracture risk largely resulting from significantly reduced levels of the hormone estrogen after menopause. Besides the direct negative effects of estrogen-deficiency on bone, indirect effects of altered immune status in postmenopausal women might contribute to ongoing bone destruction, as postmenopausal women often display a chronic low-grade inflammatory phenotype with altered cytokine expression and immune cell profile. In this context, it was previously shown that various immune cells interact with osteoblasts and osteoclasts either via direct cell-cell contact, or more likely via paracrine mechanisms. For example, specific subtypes of T lymphocytes express TNFα, which was shown to increase osteoblast apoptosis and to indirectly stimulate osteoclastogenesis via B cell-produced receptor-activator of NF-κB ligand (RANKL), thereby triggering bone loss during postmenopausal osteoporosis. T17 cells release interleukin-17 (IL-17), which directs mesenchymal stem cell differentiation towards the osteogenic lineage, but also indirectly increases osteoclast differentiation. B lymphocytes are a major regulator of osteoclast formation via granulocyte colony-stimulating factor secretion and the RANKL/osteoprotegerin system under estrogen-deficient conditions. Macrophages might act differently on bone cells dependent on their polarization profile and their secreted paracrine factors, which might have implications for the development of postmenopausal osteoporosis, because macrophage polarization is altered during disease progression. Likewise, neutrophils play an important role during bone homeostasis, but their over-activation under estrogen-deficient conditions contributes to osteoblast apoptosis via the release of reactive oxygen species and increased osteoclastogenesis via RANKL signaling. Furthermore, mast cells might be involved in the development of postmenopausal osteoporosis, because they store high levels of osteoclastic mediators, including IL-6 and RANKL, in their granules and their numbers are greatly increased in osteoporotic bone. Additionally, bone fracture healing is altered under estrogen-deficient conditions with the increased presence of pro-inflammatory cytokines, including IL-6 and Midkine, which might contribute to healing disturbances. Consequently, in addition to the direct negative influence of estrogen-deficiency on bone, immune cell alterations contribute to the pathogenesis of postmenopausal osteoporosis.
Topics: Bone Resorption; Bone and Bones; Cell Differentiation; Estrogens; Female; Humans; Osteoblasts; Osteoclasts; Osteoporosis, Postmenopausal
PubMed: 34024716
DOI: 10.1016/j.semcdb.2021.05.014 -
Journal of Bone and Mineral Research :... Mar 2023Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and... (Review)
Review
Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and bone formation during remodeling crucially maintains skeletal mass. Increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells. Herein, we discuss the origin and functions for macrophages in the bone microenvironment, tissue resident macrophages, osteomacs, as well as newly identified osteomorphs that result from osteoclast fission. We also touch on the role of macrophages during inflammatory bone resorption. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Cell Differentiation; Bone Remodeling; Osteoclasts; Macrophages; Bone Resorption; Osteoblasts; Osteogenesis
PubMed: 36651575
DOI: 10.1002/jbmr.4773 -
Cell Mar 2021Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once...
Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.
Topics: Animals; Apoptosis; Bone Resorption; Cell Fusion; Cells, Cultured; Humans; Macrophages; Mice; Osteochondrodysplasias; Osteoclasts; RANK Ligand; Signal Transduction
PubMed: 33636130
DOI: 10.1016/j.cell.2021.02.002 -
Nature Communications Jan 2020Wolff's law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat...
Wolff's law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive. Here, we find that Piezo1 deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. Furthermore, Piezo1-deficient mice are resistant to further bone loss and bone resorption induced by hind limb unloading, demonstrating that PIEZO1 can affect osteoblast-osteoclast crosstalk in response to mechanical forces. At the mechanistic level, in response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. In turn, these collagen isoforms regulate osteoclast differentiation. Taken together, our data identify PIEZO1 as the major skeletal mechanosensor that tunes bone homeostasis.
Topics: Animals; Bone Resorption; Cell Differentiation; Collagen Type II; Collagen Type IX; Female; Fractures, Bone; Hindlimb Suspension; Homeostasis; Ion Channels; Male; Mice, Knockout; Osteoblasts; Osteoclasts; Osteoporosis; Stress, Mechanical
PubMed: 31941964
DOI: 10.1038/s41467-019-14146-6 -
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 -
Cells Jul 2022Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with... (Review)
Review
Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with associated osteolytic lesions is a hallmark of MM and develops in the majority of MM patients. Approximately half of patients with bone disease will experience skeletal-related events (SREs), such as spinal cord compression and pathologic fractures, which increase the risk of mortality by 20-40%. At the cellular level, bone disease results from a tumor-cell-driven imbalance between osteoclast bone resorption and osteoblast bone formation, thereby creating a favorable cellular environment for bone resorption. The use of osteoclast inhibitory therapies with bisphosphonates, such as zoledronic acid and the RANKL inhibitor denosumab, have been shown to delay and lower the risk of SREs, as well as the need for surgery or radiation therapy to treat severe bone complications. This review outlines our current understanding of the molecular underpinnings of bone disease, available therapeutic options, and highlights recent advances in the management of MM-related bone disease.
Topics: Biological Products; Bone Neoplasms; Bone Resorption; Diphosphonates; Humans; Multiple Myeloma
PubMed: 35954151
DOI: 10.3390/cells11152308 -
Annual Review of Pathology Jan 2023Osteoclasts are multinucleated cells with the unique ability to resorb bone matrix. Excessive production or activation of osteoclasts leads to skeletal pathologies that... (Review)
Review
Osteoclasts are multinucleated cells with the unique ability to resorb bone matrix. Excessive production or activation of osteoclasts leads to skeletal pathologies that affect a significant portion of the population. Although therapies that effectively target osteoclasts have been developed, they are associated with sometimes severe side effects, and a fuller understanding of osteoclast biology may lead to more specific treatments. Along those lines, a rich body of work has defined essential signaling pathways required for osteoclast formation, function, and survival. Nonetheless, recent studies have cast new light on long-held views regarding the origin of these cells during development and homeostasis, their life span, and the cellular sources of factors that drive their production and activity during homeostasis and disease. In this review, we discuss these new findings in the context of existing work and highlight areas of ongoing and future investigation.
Topics: Humans; Osteoclasts; Bone Resorption; Signal Transduction; Cell Differentiation
PubMed: 36207010
DOI: 10.1146/annurev-pathmechdis-031521-040919 -
International Journal of Molecular... Nov 2019Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny,... (Review)
Review
Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed.
Topics: Animals; Bone Remodeling; Bone Resorption; Bone and Bones; Humans; Osteogenesis; Phenotype; Wnt Signaling Pathway
PubMed: 31698687
DOI: 10.3390/ijms20225525