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International Journal of Cancer Aug 2015Bisphosphonates are osteoclast inhibitors, currently being used in oncology to prevent or delay bone morbidity in cancer. Oral and intravenous formulations of... (Review)
Review
Bisphosphonates are osteoclast inhibitors, currently being used in oncology to prevent or delay bone morbidity in cancer. Oral and intravenous formulations of bisphosphonates have been found to be efficacious in preventing skeletal-related events such as bone pain, pathologic fractures, spinal cord compression and hypercalcemia of malignancy, in patients with bone metastatic breast cancer. Bisphosphonates are also used to prevent bone loss associated with anti-estrogen therapy using aromatase inhibitors. In addition to its role in preventing bone resorption, several pre-clinical studies have noted an anti-tumor role as well. Recent research effort has particularly focused on investigating an adjuvant role for bisphosphonates in early breast cancer. Recently, few randomized trials have found a beneficial effect for adjuvant use of the aminobisphosphonate, zoledronate, in older patients who are post-menopausal. This review article will summarize the various clinical studies investigating the role of bisphosphonates in breast cancer.
Topics: Aromatase Inhibitors; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Diphosphonates; Female; Humans
PubMed: 24824552
DOI: 10.1002/ijc.28965 -
Theranostics 2021Bone homeostasis is maintained by a balanced interplay of osteoblasts and osteoclasts. Osteoclasts are derived from monocyte/macrophage lineage. Major vault protein...
Bone homeostasis is maintained by a balanced interplay of osteoblasts and osteoclasts. Osteoclasts are derived from monocyte/macrophage lineage. Major vault protein (MVP) is known to promote apoptosis and prevent metabolic diseases in macrophage. However, whether MVP is involved in osteoclastogenesis is unknown. Here, we identified an important function of MVP as a negative regulator of osteoclastogenesis and its therapeutic potential in preventing bone loss. Expression of MVP in osteoclasts was investigated in human tumor tissues with immunohistochemical staining. Next, we generated total body ( ) and monocyte-specific () MVP gene knockout mice to observe bone phenotype and osteoclastogenesis using micro-CT and bone histomorphometry. Moreover, we examined the effects of MVP on osteoclast differentiation, bone resorption, NFATc1 activation and calcium oscillations . Finally, we explored the clinical potential of targeting MVP in two osteoporosis mouse models and used an adeno-associated virus (AAV) gene to overexpress MVP locally in mice. We found that and mice both exhibited osteoporosis-like phenotypes. MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption. Calcineurin inhibition using the small molecule inhibitor FK506 corrected the enhanced osteoclastogenesis in group. Additionally, MVP reexpression in group rescued calcineurin expression. MVP overexpression in wild-type mice prevented pathologic bone loss in mouse models of ovariectomized (OVX) and calvaria-adjacent lipopolysaccharide (LPS)-injected. Our data suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling. In osteoclast-related bone diseases such as osteoporosis, manipulation of MVP activity may be an attractive therapeutic target.
Topics: Animals; Bone Resorption; Calcineurin; Cell Differentiation; Humans; Mice; Mice, Knockout; NFATC Transcription Factors; Osteoclasts; Signal Transduction; Vault Ribonucleoprotein Particles
PubMed: 34158848
DOI: 10.7150/thno.58468 -
Osteoporosis International : a Journal... Sep 2013The transcription factor NF-κB is a family of proteins involved in signaling pathways essential for normal cellular functions and development. Deletion of various... (Review)
Review
The transcription factor NF-κB is a family of proteins involved in signaling pathways essential for normal cellular functions and development. Deletion of various components of this pathway resulted with abnormal skeletal development. Research in the last decade has established that NF-κB signaling mediates RANK ligand-induced osteoclastogenesis. Consistently, it was shown that inhibition of NF-κB was an effective approach to inhibit osteoclast formation and bone resorptive activity. Identification of the molecular machinery underlying NF-κB activation permitted osteoclast-specific deletion of the major components of this pathway. As a result, it was clear that deletion of members of the proximal IKK kinase complex and the distal NF-κB subunits and downstream regulators affected skeletal development. These studies provided several targets of therapeutic intervention in osteolytic diseases. NF-κB activity has been also described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. Indeed, inflammatory insults exacerbate physiologic RANKL-induced NF-κB signals leading to exaggerated responses and to inflammatory osteolysis. These superimposed NF-κB activities appear to underlie several bone pathologies. This review will describe the individual roles of NF-κB molecules in bone resorption and inflammatory osteolysis.
Topics: Bone Resorption; Humans; NF-kappa B; Osteitis Deformans; Osteoclasts; Osteolysis; Periodontitis; Signal Transduction
PubMed: 23468073
DOI: 10.1007/s00198-013-2313-x -
Operative Neurosurgery (Hagerstown, Md.) Apr 2021Following a decompressive craniectomy, the autologous bone flap is generally considered the reconstructive material of choice in pediatric patients. Replacement of the... (Review)
Review
Following a decompressive craniectomy, the autologous bone flap is generally considered the reconstructive material of choice in pediatric patients. Replacement of the original bone flap takes advantage of its natural biocompatibility and the associated low risk of rejection, as well as the potential to reintegrate with the adjacent bone and subsequently grow with the patient. However, despite these advantages and unlike adult patients, the replaced calvarial bone is more likely to undergo delayed bone resorption in pediatric patients, ultimately requiring revision surgery. In this review, we describe the materials that are currently available for pediatric cranioplasty, the advantages and disadvantages of autologous calvarial replacement, the incidence and classification of bone resorption, and the clinical risk factors for bone flap resorption that have been identified to date.
Topics: Adult; Bone Resorption; Child; Decompressive Craniectomy; Humans; Retrospective Studies; Skull; Surgical Flaps
PubMed: 33469664
DOI: 10.1093/ons/opaa452 -
BioMed Research International 2022Bone remodels via resorption and formation, two phenomena that continuously occur in bone turnover. The RANKL/RANK/OPG pathway is one of the several mechanisms that... (Review)
Review
Bone remodels via resorption and formation, two phenomena that continuously occur in bone turnover. The RANKL/RANK/OPG pathway is one of the several mechanisms that affect bone turnover. The RANKL/OPG ratio has a substantial role in bone resorption. An imbalance between formation and resorption is related to an increased RANKL/OPG balance. OPG, a member of this system, can bind to RANKL and suppress RANK-RANKL interaction, and subsequently, inhibit further osteoclastogenesis. The serum levels of RANKL and OPG in the bone microenvironment are vital for osteoclasts formation. The RANK/RANKL/OPG system plays a role in the pathogenesis of bone disorders. This system can be considered a new treatment target for bone disorders. Soy isoflavones affect the RANK/RANKL/OPG system through numerous mechanisms. Soy isoflavones decrease RANKL levels and increase OPG levels. Therefore, isoflavones improve bone metabolism and decrease bone resorption. Soy isoflavones decrease serum markers of bone resorption and improve bone metabolism. However, while the available data are promising, the results of several studies reported no change in RANKL and OPG levels with isoflavones supplementation. In this regard, current evidence is insufficient for conclusive approval of the efficacy of isoflavones on RANKL/RANK/OPG and further research, including animal and human studies, are needed to confirm the effect of soy isoflavones on the RANKL/RANK/OPG pathway. This study was a review of available evidence to determine the role of isoflavones in bone hemostasis and the RANK/RANKL/OPG pathway. The identification of the effects of isoflavones on the RANKL/RANK/OPG pathway directs future studies and leads to the development of effective treatment strategies for bone disorders.
Topics: Animals; Humans; Receptor Activator of Nuclear Factor-kappa B; Osteoprotegerin; Bone Density; RANK Ligand; Bone Resorption; Osteoclasts; Bone Diseases; Isoflavones
PubMed: 36330454
DOI: 10.1155/2022/8862278 -
International Journal of Molecular... Jan 2022Transforming growth factor-beta (TGF-β) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been... (Review)
Review
Transforming growth factor-beta (TGF-β) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-β from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-β from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-β may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-β. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-β release in the pathogenesis of muscle wasting needs to be investigated.
Topics: Animals; Bone Resorption; Humans; Muscle Proteins; Muscular Atrophy; Reactive Oxygen Species; Transforming Growth Factor beta
PubMed: 35163088
DOI: 10.3390/ijms23031167 -
Biological Chemistry Jan 2022Bone metabolism is essential for maintaining bone mineral density and bone strength through a balance between bone formation and bone resorption. Bone formation is... (Review)
Review
Bone metabolism is essential for maintaining bone mineral density and bone strength through a balance between bone formation and bone resorption. Bone formation is associated with osteoblast activity whereas bone resorption is linked to osteoclast differentiation. Osteoblast progenitors give rise to the formation of mature osteoblasts whereas monocytes are the precursors for multi-nucleated osteoclasts. Chronic inflammation, auto-inflammation, hormonal changes or adiposity have the potential to disturb the balance between bone formation and bone loss. Several plant-derived components are described to modulate bone metabolism and alleviate osteoporosis by enhancing bone formation and inhibiting bone resorption. The plant-derived naphthoquinone plumbagin is a bioactive compound that can be isolated from the roots of the genus. It has been used as traditional medicine for treating infectious diseases, rheumatoid arthritis and dermatological diseases. Reportedly, plumbagin exerts its biological activities primarily through induction of reactive oxygen species and triggers osteoblast-mediated bone formation. It is plausible that plumbagin's reciprocal actions - inhibiting or inducing death in osteoclasts but promoting survival or growth of osteoblasts - are a function of the synergy with bone-metabolizing hormones calcitonin, Parathormone and vitamin D. Herein, we develop a framework for plausible molecular of plumbagin in bone metabolism.
Topics: Bone Resorption; Cell Differentiation; Humans; Inflammation; Naphthoquinones; Osteoblasts; Osteoclasts; Phytochemicals
PubMed: 34882360
DOI: 10.1515/hsz-2021-0290 -
Seminars in Cell & Developmental Biology Jan 2016The teleologic link between increased production of pro-inflammatory cytokines resulting from a systemic inflammatory response to a burn injury and consequent... (Review)
Review
The teleologic link between increased production of pro-inflammatory cytokines resulting from a systemic inflammatory response to a burn injury and consequent stimulation of bone resorption is unclear. While it is known that cytokines can stimulate osteocytic and osteoblastic production of the ligand of the receptor activator of NFκB, or RANKL, it is not certain why this occurs. It was therefore hypothesized that the subsequent osteoclastic bone resorption liberates calcium from the bone matrix and somehow affects the inflammatory response. In this paper we show how the cytokine-mediated inflammatory response following severe burn injury in children results in simultaneous increase in bone resorption and up-regulation of the parathyroid calcium-sensing receptor. The acute bone resorption leads to release of calcium from the bone matrix with consequent calcium accumulation in the circulation. The up-regulation of the parathyroid calcium-sensing receptor suppresses the release of parathyroid hormone resulting in a lowering of blood calcium concentration. The simultaneous occurrences of these processes could regulate blood calcium concentration and if calcium concentration affects the inflammatory response, then the calcium-sensing receptor could, at the very least, modulate the inflammatory response by adjusting the blood calcium concentration. We describe in vitro studies in which we demonstrated that peripheral blood mononuclear cells in culture produce the chemokines MIP-1α and RANTES in proportion to the medium calcium concentration and they produce the chemokine MCP-1 in quantities inversely related to medium calcium concentration. CD14+monocytes in culture will also produce MIP-1α in direct relationship to medium calcium concentration but the correlation coefficient is markedly reduced compared to that with peripheral blood mononuclear cells. These monocytes, which possess the calcium-sensing receptor, do not produce MCP-1 in either direct or inverse relationship to medium calcium concentration. Therefore, it is possible that other peripheral blood mononuclear cells are primarily responsible for the production of chemokines in relation to calcium concentration but these cells have not yet been defined.
Topics: Animals; Bone Resorption; Burns; Calcium; Cytokines; Humans; Inflammation; Leukocytes, Mononuclear; Receptors, Calcium-Sensing
PubMed: 26303192
DOI: 10.1016/j.semcdb.2015.08.006 -
International Journal of Molecular... Jun 2021Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating... (Review)
Review
Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.
Topics: Animals; Bone Neoplasms; Bone Remodeling; Bone Resorption; Cell Communication; Disease Progression; Disease Susceptibility; Humans; Osteoclasts; Osteogenesis; Osteosarcoma
PubMed: 34202300
DOI: 10.3390/ijms22136865 -
Frontiers in Endocrinology 2020TNF (Tumor necrosis factor) is a pleiotropic cytokine that plays an important role in immunity and inflammatory bone destruction. Homeostatic osteoclastogenesis is... (Review)
Review
TNF (Tumor necrosis factor) is a pleiotropic cytokine that plays an important role in immunity and inflammatory bone destruction. Homeostatic osteoclastogenesis is effectively induced by RANKL (Receptor activator of nuclear factor kappa-B ligand). In contrast, TNF often acts on cell types other than osteoclasts, or synergically with RANKL to indirectly promote osteoclastogenesis and bone resorption. TNF and RANKL are members of the TNF superfamily. However, the direct osteoclastogenic capacity of TNF is much weaker than that of RANKL. Recent studies have uncovered key intrinsic mechanisms by which TNF acts on osteoclast precursors to restrain osteoclastogenesis, including the mechanisms mediated by RBP-J signaling, RBP-J and ITAM (Immunoreceptor tyrosine-based activation motif) crosstalk, RBP-J mediated regulatory network, NF-B p100, IRF8, and Def6. Some of these mechanisms, such as RBP-J and its mediated regulatory network, uniquely and predominantly limit osteoclastogenesis mediated by TNF but not by RANKL. As a consequence, targeting RBP-J activities suppresses inflammatory bone destruction but does not significantly impact normal bone remodeling or inflammation. Hence, discovery of these intrinsic inhibitory mechanisms addresses why TNF has a weak osteoclastogenic potential, explains a significant difference between RANKL and TNF signaling, and provides potentially new or complementary therapeutic strategies to selectively treat inflammatory bone resorption, without undesirable effects on normal bone remodeling or immune response in disease settings.
Topics: Animals; Bone Resorption; Cell Differentiation; Humans; Inflammation; Osteogenesis; Tumor Necrosis Factor-alpha
PubMed: 33133025
DOI: 10.3389/fendo.2020.583561