Thrombospondins in bone remodeling and metastatic bone disease

2020 ◽  
Vol 319 (6) ◽  
pp. C980-C990
Author(s):  
Laura Carminati ◽  
Giulia Taraboletti
Keyword(s):  
Bone Metastasis ◽  
Bone Remodeling ◽  
Cancer Metastasis ◽  
Bone Cells ◽  
Bone Homeostasis ◽  
Matricellular Proteins ◽  
Metastatic Niche ◽  
Tissue Microenvironment ◽  
Pathological Conditions ◽  
Wide Range

Thrombospondins (TSPs) are a family of five multimeric matricellular proteins. Through a wide range of interactions, TSPs play pleiotropic roles in embryogenesis and in tissue remodeling in adult physiology as well as in pathological conditions, including cancer development and metastasis. TSPs are active in bone remodeling, the process of bone resorption (osteolysis) and deposition (osteogenesis) that maintains bone homeostasis. TSPs are particularly involved in aberrant bone remodeling, including osteolytic and osteoblastic skeletal cancer metastasis, frequent in advanced cancers such as breast and prostate carcinoma. TSPs are major players in the bone metastasis microenvironment, where they finely tune the cross talk between tumor cells and bone resident cells in the metastatic niche. Each TSP family member has different effects on the differentiation and activity of bone cells—including the bone-degrading osteoclasts and the bone-forming osteoblasts—with different outcomes on the development and growth of osteolytic and osteoblastic metastases. Here, we overview the involvement of TSP family members in the bone tissue microenvironment, focusing on their activity on osteoclasts and osteoblasts in bone remodeling, and present the evidence to date of their roles in bone metastasis establishment and growth.

scholarly journals Impact of the Autonomic Nervous System on the Skeleton

2018 ◽  
Vol 98 (3) ◽  
pp. 1083-1112 ◽  
Author(s):  
Florent Elefteriou
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cancer Metastasis ◽  
Bone Development ◽  
Autonomic Nerves ◽  
Bone Homeostasis ◽  
Bone Mass Accrual ◽  
The Central Nervous System

It is from the discovery of leptin and the central nervous system as a regulator of bone remodeling that the presence of autonomic nerves within the skeleton transitioned from a mere histological observation to the mechanism whereby neurons of the central nervous system communicate with cells of the bone microenvironment and regulate bone homeostasis. This shift in paradigm sparked new preclinical and clinical investigations aimed at defining the contribution of sympathetic, parasympathetic, and sensory nerves to the process of bone development, bone mass accrual, bone remodeling, and cancer metastasis. The aim of this article is to review the data that led to the current understanding of the interactions between the autonomic and skeletal systems and to present a critical appraisal of the literature, bringing forth a schema that can put into physiological and clinical context the main genetic and pharmacological observations pointing to the existence of an autonomic control of skeletal homeostasis. The different types of nerves found in the skeleton, their functional interactions with bone cells, their impact on bone development, bone mass accrual and remodeling, and the possible clinical or pathophysiological relevance of these findings are discussed.

scholarly journals Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Rinaldo Florencio-Silva ◽  
Gisela Rodrigues da Silva Sasso ◽  
Estela Sasso-Cerri ◽  
Manuel Jesus Simões ◽  
Paulo Sérgio Cerri
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Tissue ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Current Data ◽  
Bone Diseases ◽  
Bone Homeostasis ◽  
Bone Biology ◽  
Structure And Functions

Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.

scholarly journals The Influence of Radiation on Bone and Bone Cells—Differential Effects on Osteoclasts and Osteoblasts

2020 ◽  
Vol 21 (17) ◽  
pp. 6377
Author(s):  
Anna-Jasmina Donaubauer ◽  
Lisa Deloch ◽  
Ina Becker ◽  
Rainer Fietkau ◽  
Benjamin Frey ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Bone Cells ◽  
Positive Impact ◽  
Inflammatory Diseases ◽  
Future Research ◽  
Special Focus ◽  
Bone Homeostasis ◽  
Bone Microenvironment

The bone is a complex organ that is dependent on a tight regulation between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs). These processes can be influenced by environmental factors such as ionizing radiation (IR). In cancer therapy, IR is applied in high doses, leading to detrimental effects on bone, whereas radiation therapy with low doses of IR is applied for chronic degenerative and inflammatory diseases, with a positive impact especially on bone homeostasis. Moreover, the effects of IR are of particular interest in space travel, as astronauts suffer from bone loss due to space radiation and microgravity. This review summarizes the current state of knowledge on the effects of IR on bone with a special focus on the influence on OCs and OBs, as these cells are essential in bone remodeling. In addition, the influence of IR on the bone microenvironment is discussed. In summary, the effects of IR on bone and bone remodeling cells strongly depend on the applied radiation dose, as differential results are provided from in vivo as well as in vitro studies with varying doses of IR. Furthermore, the isolated effects of IR on a single cell type are difficult to determine, as the bone cells and bone microenvironment are building a tightly regulated network, influencing on one another. Therefore, future research is necessary in order to elucidate the influence of different bone cells on the overall radiation-induced effects on bone.

Cellular Communication in Bone Homeostasis and the Related Anti-osteoporotic Drug Development

2020 ◽  
Vol 27 (7) ◽  
pp. 1151-1169 ◽  
Author(s):  
Yi Zhang ◽  
Guojing Luo ◽  
Xijie Yu
Keyword(s):  
Drug Development ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Bone Diseases ◽  
Cellular Communication ◽  
New Drugs ◽  
Complex Signal ◽  
Bone Homeostasis ◽  
Metabolic Bone Diseases ◽  
Signal Network

Background: Intercellular crosstalk among osteoblast, osteoclast, osteocyte and chondrocyte is involved in the precise control of bone homeostasis. Disruption of this cellular and molecular signaling would lead to metabolic bone diseases such as osteoporosis. Currently a number of anti-osteoporosis interventions are restricted by side effects, complications and long-term intolerance. This review aims to summarize the bone cellular communication involved in bone remodeling and its usage to develop new drugs for osteoporosis. Methods: We searched PubMed for publications from 1 January 1980 to 1 January 2018 to identify relevant and latest literatures, evaluation and prospect of osteoporosis medication were summarized. Detailed search terms were ‘osteoporosis’, ‘osteocyte’, ‘osteoblast’, ‘osteoclast’, ‘bone remodeling’, ‘chondrocyte’, ‘osteoporosis treatment’, ‘osteoporosis therapy’, ‘bisphosphonates’, ‘denosumab’, ‘Selective Estrogen Receptor Modulator (SERM)’, ‘PTH’, ‘romosozumab’, ‘dkk-1 antagonist’, ‘strontium ranelate’. Results: A total of 170 papers were included in the review. About 80 papers described bone cell interactions involved in bone remodeling. The remaining papers were focused on the novel advanced and new horizons in osteoporosis therapies. Conclusion: There exists a complex signal network among bone cells involved in bone remodeling. The disorder of cell-cell communications may be the underlying mechanism of osteoporosis. Current anti-osteoporosis therapies are effective but accompanied by certain drawbacks simultaneously. Restoring the abnormal signal network and individualized therapy are critical for ideal drug development.

scholarly journals Restoring Tissue Homeostasis at Metastatic Sites: A Focus on Extracellular Vesicles in Bone Metastasis

2021 ◽  
Vol 11 ◽  
Author(s):  
Domenica Giannandrea ◽  
Valentina Citro ◽  
Elena Lesma ◽  
Monica Bignotto ◽  
Natalia Platonova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Metastasis ◽  
Extracellular Vesicles ◽  
Cancer Metastasis ◽  
Bone Marrow Niche ◽  
Bone Homeostasis ◽  
Metastasis Formation ◽  
Tumor Dissemination ◽  
Increased Risk

Bone is the most common site of cancer metastasis and the spread of cancer cells to the bone is associated with poor prognosis, pain, increased risk of fractures, and hypercalcemia. The bone marrow microenvironment is an attractive place for tumor dissemination, due to the dynamic network of non-malignant cells. In particular, the alteration of the bone homeostasis favors the tumor homing and the consequent osteolytic or osteoblastic lesions. Extracellular vesicles (EVs) are reported to be involved in the metastatic process, promoting tumor invasion, escape from immune surveillance, extravasation, extracellular matrix remodeling, and metastasis, but the role of EVs in bone metastases is still unclear. Current results suggest the ability of tumor derived EVs in promoting bone localization and metastasis formation, altering the physiological balance between bone destruction and new bone depositions. Moreover, EVs from the bone marrow niche may support the onset of tumor metastasis. This review summarizes recent findings on the role of EVs in the pathological alterations of homeostasis that occur during bone metastasis to show novel potential EV-based therapeutic options to inhibit metastasis formation.

Microfluidic platform for studying osteocyte mechanoregulation of breast cancer bone metastasis

2019 ◽  
Vol 11 (4) ◽  
pp. 119-129 ◽  
Author(s):  
Xueting Mei ◽  
Kevin Middleton ◽  
Dongsub Shim ◽  
Qianqian Wan ◽  
Liangcheng Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fluid Flow ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Remodeling ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Intervention Strategy ◽  
Side Channels ◽  
Breast Cancer Bone Metastasis

AbstractBone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.

scholarly journals Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yingru Xu ◽  
Shuxia Zhang ◽  
Xinyi Liao ◽  
Man Li ◽  
Suwen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Bone Remodeling ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Metastatic Niche ◽  
Breast Cancer Bone Metastasis

Abstract Background Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. Methods Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. Results We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. Conclusion We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

scholarly journals JAK/STAT pathway and molecular mechanism in bone remodeling

2020 ◽  
Vol 47 (11) ◽  
pp. 9087-9096
Author(s):  
Eliana Rita Sanpaolo ◽  
Cinzia Rotondo ◽  
Daniela Cici ◽  
Ada Corrado ◽  
Francesco Paolo Cantatore
Keyword(s):  
Bone Remodeling ◽  
Molecular Mechanism ◽  
Target Genes ◽  
Bone Cells ◽  
Cell Types ◽  
Bone Homeostasis ◽  
Signal Cascade ◽  
Proliferation And Differentiation ◽  
Stat Pathway

AbstractJAK/STAT signaling pathway is involved in many diseases, including autoimmune diseases, which are characterized by a close interconnection between immune and bone system. JAK/STAT pathway is involved in bone homeostasis and plays an important role in proliferation and differentiation of some cell types, including osteoblasts and osteoclasts. Different molecules, such as cytokines, hormones, and growth factors are responsible for the activation of the JAK/STAT pathway, which leads, at the nuclear level, to start DNA transcription of target genes. Bone cells and remodeling process are often influenced by many cytokines, which act as strong stimulators of bone formation and resorption. Our aim, through careful research in literature, has been to provide an overview of the role of the JAK/STAT pathway in bone remodeling and on bone cells, with a focus on cytokines involved in bone turnover through this signal cascade. The JAK/STAT pathway, through the signal cascade activation mediated by the interaction with many cytokines, acts on bone cells and appears to be involved in bone remodeling process. However, many other studies are needed to completely understand the molecular mechanism underlying these bone process.

Increased Concentrations of Prostaglandin D2 During Post-Fracture Bone Remodeling

2010 ◽  
Vol 37 (3) ◽  
pp. 644-649 ◽  
Author(s):  
MAXIME A. GALLANT ◽  
ESTELLE CHAMOUX ◽  
MARTINE BISSON ◽  
CATARINA WOLSEN ◽  
JEAN-LUC PARENT ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Type I Collagen ◽  
Bone Cells ◽  
Bone Alkaline Phosphatase ◽  
Positive Influence ◽  
Fracture Repair ◽  
Prostaglandin D2 ◽  
Type I ◽  
Bone Homeostasis

Objective.To test the hypothesis that increased concentrations of prostaglandin D2 (PGD2) correlate with bone remodeling. Studies using isolated bone cells indicate that PGD2 may be implicated in the regulation of bone homeostasis, with a positive influence on bone anabolism. We studied patients with traumatic fractures and age- and sex-matched healthy controls as an in vivo model of increased bone remodeling.Methods.Thirty-five patients with bone fracture and matched controls were recruited. Urine and sera samples were collected. Urinary 11ß-PGF2α, a PGD2 metabolite, and PGE2 metabolites (PGEM), serum lipocalin-type PGD2 synthase (L-PGDS), bone alkaline phosphatase (bone ALP), and crosslinked C-telopeptides of type I collagen (CTX) were measured.Results.At 5–6 weeks post-fracture, 11ß-PGF2α, L-PGDS, bone ALP, and CTX were significantly increased in the fracture patients compared to controls. PGEM levels were not different between groups. Levels of 11ß-PGF2α and bone ALP were positively correlated, suggesting that PGD2 may be implicated in fracture repair.Conclusion.These results support our working hypothesis that PGD2 could be implicated in the control of bone anabolism in humans.

scholarly journals Emerging Multifunctional Roles of Claudin Tight Junction Proteins in Bone

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2363-2376 ◽  
Author(s):  
Fatima. Z. Alshbool ◽  
Subburaman Mohan
Keyword(s):  
Tight Junction ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Cell Types ◽  
Future Research ◽  
Bone Homeostasis ◽  
Tight Junction Proteins ◽  
Regulation Of Expression ◽  
Junction Proteins

The imbalance between bone formation and resorption during bone remodeling has been documented to be a major factor in the pathogenesis of osteoporosis. Recent evidence suggests a significant role for the tight junction proteins, Claudins (Cldns), in the regulation of bone remodeling processes. In terms of function, whereas Cldns act “canonically” as key determinants of paracellular permeability, there is considerable recent evidence to suggest that Cldns also participate in cell signaling, ie, a “noncanonical function”. To this end, Cldns have been shown to regulate cell proliferation, differentiation, and gene expression in a variety of cell types. The present review will discuss Cldns’ structure, their expression profile, regulation of expression, and their canonical and non- canonical functions in general with special emphasis on bone cells. In order to shed light on the noncanonical functions of Cldns in bone, we will highlight the role of Cldn-18 in regulating bone resorption and osteoclast differentiation. Collectively, we hope to provide a framework for guiding future research on understanding how Cldns modulate osteoblast and osteoclast function and overall bone homeostasis. Such studies should provide valuable insights into the pathogenesis of osteoporosis, and may highlight Cldns as novel targets for the diagnosis and therapeutic management of osteoporosis.

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