The osteoclast, bone remodelling and treatment of metabolic bone disease

Boyce, Brendan F.; Rosenberg, Elizabeth; Papp, Anne E. de; Duong, Le T.

doi:10.1111/j.1365-2362.2012.02717.x

Cited by 157 publications

(158 citation statements)

References 79 publications

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“…54,58,59 When bone is subjected to loading, SOST expression and sclerostin levels decrease significantly, stimulating osteoblast activity and probably (through an effect on RANKL) inhibiting osteoclasts. 1,60,61 On the other hand, osteocytes have also recently been shown in vivo and in vitro to be the primary expressers of RANKL, a regulator of osteoclast differentiation and activation. 57,58,62,63 RANKL is upregulated (resulting in targeted tissue removal) when osteocytes are damaged, die by apoptosis or experience prolonged loss of mechanical loading, and recent evidence also suggest that osteocyte RANKL may be specifically involved in the remodeling process of cancellous bone.…”

Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

“…66 This suggests alternative regulation factors and/or control pathways, perhaps via osteoblast control of RANKL, although parathyroid hormone (known to promote osteoblast expression of RANKL in mammals) is present in quite different form in fishes, and fishes lack parathyroid glands. 60,67 Determination of the precise triggering and activation machineries involved, the sequence of gene expression in regulation and coordination, and the cells that take part in sensing the need for fish bone modeling can be made by a combination of histological, biochemical and molecular genetics methods. Even if the cells in the bones of fishes are shown to possess different functions than those in mammalian bone, comparison of these systems will shed invaluable new light on our understanding of bone cell biology, diversity and function.…”

Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

“…Even if the cells in the bones of fishes are shown to possess different functions than those in mammalian bone, comparison of these systems will shed invaluable new light on our understanding of bone cell biology, diversity and function. As current therapy concepts for syndromes like osteoporosis assume that osteocytes orchestrate bone formation and adaptation, 60 Outcome of three intraperitoneal injections of fluorochrome dyes in tilapia operculum loaded by orthodontic springs. The injections were made 1 week apart (day 0-calcein, day 7-alizarin red, day 14-calcein).…”

Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

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The enigmas of bone without osteocytes

Shahar¹,

Dean²

2013

BoneKEy Reports

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One of the hallmarks of tetrapod bone is the presence of numerous cells (osteocytes) within the matrix. Osteocytes are vital components of tetrapod bone, orchestrating the processes of bone building, reshaping and repairing (modeling and remodeling), and probably also participating in calcium-phosphorus homeostasis via both the local process of osteocytic osteolysis, and systemic effect on the kidneys. Given these critical roles of osteocytes, it is thought-provoking that the entire skeleton of many fishes consists of bone material that does not contain osteocytes. This raises the intriguing question of how the skeleton of these animals accomplishes the various essential functions attributed to osteocytes in other vertebrates, and raises the possibility that in acellular bone some of these functions are either accomplished by non-osteocytic routes or not necessary at all. In this review, we outline evidence for and against the fact that primary functions normally ascribed to osteocytes, such as mechanosensation, regulation of osteoblast/clast activity and mineral metabolism, also occur in fish bone devoid of these cells, and therefore must be carried out through alternative and perhaps ancient pathways. To enable meaningful comparisons with mammalian bone, we suggest thorough, phylogenetic examinations of regulatory pathways, studies of structure and mechanical properties and surveys of the presence/absence of bone cells in fishes. Insights gained into the micro-/nanolevel structure and architecture of fish bone, its mechanical properties and its physiology in health and disease will contribute to the discipline of fish skeletal biology, but may also help answer questions of basic bone biology.

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Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

See 1 more Smart Citation

The enigmas of bone without osteocytes

Shahar¹,

Dean²

2013

BoneKEy Reports

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“…Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs.…”

mentioning

confidence: 99%

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

et al. 2015

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Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca 2+ oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12 fl/fl cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. Bone homeostasis is tightly regulated by the balance between osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. 1 Pathological conditions such as osteoporosis, inflammation, and cancer break this balance in favor of the augmentation of OC activity, resulting in net bone loss. 2-4 As a result, patients with these diseases suffer from pain and risk of bone fracture. Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs. 13 Robust induction of NFAT2 is dependent on calcium (Ca 2+ ) oscillations. 14 Ca 2+ oscillations lead to calcineurin-mediated activation of NFAT2 and ensure NFAT2 long-lasting transcriptional activation. 13,14 Despite these...

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“…The human skeleton is constantly renewed and repaired by the bone remodeling process, a well-coordinated sequence of osteoclast-mediated bone resorption and osteoblast-mediated bone formation [1,2]. Anti-catabolic drugs, such as bisphosphonates (BPs), can slow down this process and shift the balance between bone formation and resorption activity by selectively affecting osteoclast function [3].…”

Section: Introductionmentioning

confidence: 99%

Does locally delivered Zoledronate influence peri-implant bone formation? – Spatio-temporal monitoring of bone remodeling in vivo

Kettenberger

Ston

Thein³

et al. 2014

Biomaterials

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a b s t r a c tBisphosphonates are known for their strong inhibitory effect on bone resorption. Their influence on bone formation however is less clear. In this study we investigated the spatio-temporal effect of locally delivered Zoledronate on peri-implant bone formation and resorption in an ovariectomized rat femoral model. A cross-linked hyaluronic acid hydrogel was loaded with the drug and applied bilaterally in predrilled holes before inserting polymer screws. Static and dynamic bone parameters were analyzed based on in vivo microCT scans performed first weekly and then biweekly. The results showed that the locally released Zoledronate boosted bone formation rate up to 100% during the first 17 days after implantation and reduced the bone resorption rate up to 1000% later on. This shift in bone remodeling resulted in an increase in bone volume fraction (BV/TV) by 300% close to the screw and 100% further away. The double effect on bone formation and resorption indicates a great potential of Zoledronateloaded hydrogel for enhancement of peri-implant bone volume which is directly linked to improved implant fixation.

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The osteoclast, bone remodelling and treatment of metabolic bone disease

Cited by 157 publications

References 79 publications

The enigmas of bone without osteocytes

The enigmas of bone without osteocytes

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

Does locally delivered Zoledronate influence peri-implant bone formation? – Spatio-temporal monitoring of bone remodeling in vivo

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