Autophagy in bone homeostasis and the onset of osteoporosis

Abstract Autophagy is an evolutionarily conserved intracellular process, in which domestic cellular components are selectively digested for the recycling of nutrients and energy. This process is indispensable for cell homeostasis maintenance and stress responses. Both genetic and functional studies have demonstrated that multiple proteins involved in autophagic activities are critical to the survival, differentiation, and functioning of bone cells, including osteoblasts, osteocytes, and osteoclasts. Dysregulation at the level of autophagic activity consequently disturbs the balance between bone formation and bone resorption and mediates the onset and progression of multiple bone diseases, including osteoporosis. This review aims to introduce the topic of autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role in the onset of osteoporosis and therapeutic potential.

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Lactoferrin in Bone Tissue Regeneration

Current Medicinal Chemistry ◽

10.2174/0929867326666190503121546 ◽

2020 ◽

Vol 27 (6) ◽

pp. 838-853 ◽

Cited By ~ 6

Author(s):

Madalina Icriverzi ◽

Valentina Dinca ◽

Magdalena Moisei ◽

Robert W. Evans ◽

Mihaela Trif ◽

...

Keyword(s):

Bone Tissue ◽

Tissue Regeneration ◽

Bone Cells ◽

Bone Diseases ◽

Biologically Active Compounds ◽

Biologically Active ◽

Bone Tissue Regeneration ◽

Bone Homeostasis ◽

Active Compounds

: Among the multiple properties exhibited by lactoferrin (Lf), its involvement in bone regeneration processes is of great interest at the present time. A series of in vitro and in vivo studies have revealed the ability of Lf to promote survival, proliferation and differentiation of osteoblast cells and to inhibit bone resorption mediated by osteoclasts. Although the mechanism underlying the action of Lf in bone cells is still not fully elucidated, it has been shown that its mode of action leading to the survival of osteoblasts is complemented by its mitogenic effect. Activation of several signalling pathways and gene expression, in an LRPdependent or independent manner, has been identified. Unlike the effects on osteoblasts, the action on osteoclasts is different, with Lf leading to a total arrest of osteoclastogenesis. : Due to the positive effect of Lf on osteoblasts, the potential use of Lf alone or in combination with different biologically active compounds in bone tissue regeneration and the treatment of bone diseases is of great interest. Since the bioavailability of Lf in vivo is poor, a nanotechnology- based strategy to improve the biological properties of Lf was developed. The investigated formulations include incorporation of Lf into collagen membranes, gelatin hydrogel, liposomes, loading onto nanofibers, porous microspheres, or coating onto silica/titan based implants. Lf has also been coupled with other biologically active compounds such as biomimetic hydroxyapatite, in order to improve the efficacy of biomaterials used in the regulation of bone homeostasis. : This review aims to provide an up-to-date review of research on the involvement of Lf in bone growth and healing and on its use as a potential therapeutic factor in bone tissue regeneration.

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The Emerging Role of MicroRNAs in Bone Diseases and Their Therapeutic Potential

Molecules ◽

10.3390/molecules27010211 ◽

2021 ◽

Vol 27 (1) ◽

pp. 211

Author(s):

Luis Alberto Bravo Vázquez ◽

Mariana Yunuen Moreno Becerril ◽

Erick Octavio Mora Hernández ◽

Gabriela García de León Carmona ◽

María Emilia Aguirre Padilla ◽

...

Keyword(s):

Bone Growth ◽

Bone Cells ◽

Therapeutic Potential ◽

Regulation Of Gene Expression ◽

Bone Diseases ◽

Osteosarcoma Cell ◽

Main Function ◽

Altered Expression ◽

Rna Molecules ◽

Wide Range

MicroRNAs (miRNAs) are a class of small (20–24 nucleotides), highly conserved, non-coding RNA molecules whose main function is the post-transcriptional regulation of gene expression through sequence-specific manners, such as mRNA degradation or translational repression. Since these key regulatory molecules are implicated in several biological processes, their altered expression affects the preservation of cellular homeostasis and leads to the development of a wide range of pathologies. Over the last few years, relevant investigations have elucidated that miRNAs participate in different stages of bone growth and development. Moreover, the abnormal expression of these RNA molecules in bone cells and tissues has been significantly associated with the progression of numerous bone diseases, including osteoporosis, osteosarcoma, osteonecrosis and bone metastasis, among others. In fact, miRNAs regulate multiple pathological mechanisms, including altering either osteogenic or osteoblast differentiation, metastasis, osteosarcoma cell proliferation, and bone loss. Therefore, in this present review, aiming to impulse the research arena of the biological implications of miRNA transcriptome in bone diseases and to explore their potentiality as a theragnostic target, we summarize the recent findings associated with the clinical significance of miRNAs in these ailments.

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

BioMed Research International ◽

10.1155/2015/421746 ◽

2015 ◽

Vol 2015 ◽

pp. 1-17 ◽

Cited By ~ 424

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.

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β2-Adrenergic Receptor Signaling in Osteoblasts Contributes to the Catabolic Effect of Glucocorticoids on Bone

Endocrinology ◽

10.1210/en.2010-0881 ◽

2011 ◽

Vol 152 (4) ◽

pp. 1412-1422 ◽

Cited By ~ 35

Author(s):

Yun Ma ◽

Jeffry S. Nyman ◽

Huan Tao ◽

Heather H. Moss ◽

Xiangli Yang ◽

...

Keyword(s):

Bone Loss ◽

Bone Cells ◽

Sympathetic Nerves ◽

Bone Diseases ◽

Autonomic Nerves ◽

High Dose ◽

Bone Homeostasis ◽

Adrenergic Stimulation

Abstract The sympathetic nervous system is a physiological regulator of bone homeostasis. Autonomic nerves are indeed present in bone, bone cells express the β2-adrenergic receptors (β2AR), and pharmacological or genetic disruption of sympathetic outflow to bone induces bone gain in rodents. These recent findings implied that conditions that affect β2AR signaling in osteoblasts and/or sympathetic drive to bone may contribute to bone diseases. In this study, we show that dexamethasone stimulates the expression of the β2AR in differentiated primary calvarial osteoblasts, as measured by an increase in Adrβ2 mRNA and β2AR protein level after short-term dexamethasone treatment. Isoproterenol-induced cAMP accumulation and the expression of the β2AR target gene Rankl were also significantly increased after dexamethasone pretreatment, indicating that dexamethasone promotes the responsiveness of differentiated osteoblasts to adrenergic stimulation. These in vitro results led to the hypothesis that glucocorticoid-induced bone loss, provoked by increased endogenous or high-dose exogenous glucocorticoids given for the treatment of inflammatory diseases, might, at least in part, be mediated by increased sensitivity of bone-forming cells to the tonic inhibitory effect of sympathetic nerves on bone formation or their stimulatory effect on bone resorption. Supporting this hypothesis, both pharmacological and genetic β2AR blockade in mice significantly reduced the bone catabolic effect of high-dose prednisolone in vivo. This study emphasizes the importance of sympathetic nerves in the regulation of bone homeostasis and indicates that this neuroskeletal signaling axis can be modulated by hormones or drugs and contribute to enhance pathological bone loss.

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

Current Medicinal Chemistry ◽

10.2174/0929867325666180801145614 ◽

2020 ◽

Vol 27 (7) ◽

pp. 1151-1169 ◽

Cited By ~ 1

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.

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The Osteocyte as a Signaling Cell

Physiological Reviews ◽

10.1152/physrev.00043.2020 ◽

2021 ◽

Author(s):

Jesus Medical Delgado-Calle ◽

Teresita Bellido

Keyword(s):

Bone Cells ◽

Bone Matrix ◽

Bone Diseases ◽

Bone Homeostasis ◽

Marrow Fat ◽

Effector Cells ◽

Beneficial Effects ◽

Mineralized Bone Matrix ◽

And Function ◽

Endocrine Signaling

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 as well as in distant tissues. Osteocytes are a significant source of molecules that regulate bone homeostasis by integrating mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of 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 various bone therapeutics used in the clinic. Herein, 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 hematological and metastatic cancers in the skeleton.

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Molecular Signaling Pathways and Essential Metabolic Elements in Bone Remodeling: An Implication of Therapeutic Targets for Bone Diseases

Current Drug Targets ◽

10.2174/1389450121666200910160404 ◽

2020 ◽

Vol 22 (1) ◽

pp. 77-104

Author(s):

Aditi Sharma ◽

Lalit Sharma ◽

Rohit Goyal

Keyword(s):

Signaling Pathways ◽

Type I Collagen ◽

Bone Cells ◽

Bone Remodelling ◽

Cathepsin K ◽

Bone Diseases ◽

Type I ◽

Molecular Signaling ◽

Bone Homeostasis

: Bone is one of the dynamic tissues in the human body that undergoes continuous remodelling through subsequent actions of bone cells, osteoclasts, and osteoblasts. Several signal transduction pathways are involved in the transition of mesenchymal stem cells into osteoblasts. These primarily include Runx2, ATF4, Wnt signaling and sympathetic signalling. The differentiation of osteoclasts is controlled by M-CSF, RANKL, and costimulatory signalling. It is well known that bone remodelling is regulated through receptor activator of nuclear factor-kappa B ligand followed by the binding to RANK, which eventually induces the differentiation of osteoclasts. The resorbing osteoclasts secrete TRAP, cathepsin K, MMP-9 and gelatinase to digest the proteinaceous matrix of type I collagen and form a saucer-shaped lacuna along with resorption tunnels in the trabecular bone. Osteoblasts secrete a soluble decoy receptor, osteoprotegerin that prevents the binding of RANK/RANKL and thus moderating osteoclastogenesis. Moreover, bone homeostasis is also regulated by several growth factors, cytokines, calciotropic hormones, parathyroid hormone and sex steroids. The current review presents a correlation of the probable molecular targets underlying the regulation of bone mass and the role of essential metabolic elements in bone remodelling. Targeting these signaling pathways may help design newer therapies for treating bone diseases.

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Glutamine Metabolism Is Essential for Stemness of Bone Marrow Mesenchymal Stem Cells and Bone Homeostasis

Stem Cells International ◽

10.1155/2019/8928934 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Tao Zhou ◽

Yuqing Yang ◽

Qianming Chen ◽

Liang Xie

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Cells ◽

Mammalian Target Of Rapamycin ◽

Bone Diseases ◽

The Body ◽

Glutamine Metabolism ◽

Bone Homeostasis ◽

Bone Mesenchymal Stem Cells ◽

Matrix Mineralization

Skeleton has emerged as an endocrine organ which is both capable of regulating energy metabolism and being a target for it. Glutamine is the most bountiful and flexible amino acid in the body which provides adenosine 5′-triphosphate (ATP) demands for cells. Emerging evidences support that glutamine which acts as the second metabolic regulator after glucose exerts crucial roles in bone homeostasis at cellular level, including the lineage allocation and proliferation of bone mesenchymal stem cells (BMSCs), the matrix mineralization of osteoblasts, and the biosynthesis in chondrocytes. The integrated mechanism consisting of WNT, mammalian target of rapamycin (mTOR), and reactive oxygen species (ROS) signaling pathway in a glutamine-dependent pattern is responsible to regulate the complex intrinsic biological process, despite more extensive molecules are deserved to be elucidated in glutamine metabolism further. Indeed, dysfunctional glutamine metabolism enhances the development of degenerative bone diseases, such as osteoporosis and osteoarthritis, and glutamine or glutamine progenitor supplementation can partially restore bone defects which may promote treatment of bone diseases, although the mechanisms are not quite clear. In this review, we will summarize and update the latest research findings and clinical trials on the crucial regulatory roles of glutamine metabolism in BMSCs and BMSC-derived bone cells, also followed with the osteoclasts which are important in bone resorption.

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Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.644986 ◽

2021 ◽

Vol 9 ◽

Author(s):

Amy B. P. Ribet ◽

Pei Ying Ng ◽

Nathan J. Pavlos

Keyword(s):

Membrane Transport ◽

Therapeutic Potential ◽

Osteoclast Differentiation ◽

Transport Proteins ◽

Bone Diseases ◽

Bone Homeostasis ◽

Metabolic Bone Diseases ◽

Membrane Transport Proteins ◽

Metabolic Bone ◽

Gated Channel

During bone resorption, the osteoclast must sustain an extraordinarily low pH environment, withstand immense ionic pressures, and coordinate nutrient and waste exchange across its membrane to sustain its unique structural and functional polarity. To achieve this, osteoclasts are equipped with an elaborate set of membrane transport proteins (pumps, transporters and channels) that serve as molecular ‘gatekeepers’ to regulate the bilateral exchange of ions, amino acids, metabolites and macromolecules across the ruffled border and basolateral domains. Whereas the importance of the vacuolar-ATPase proton pump and chloride voltage-gated channel 7 in osteoclasts has long been established, comparatively little is known about the contributions of other membrane transport proteins, including those categorized as secondary active transporters. In this Special Issue review, we provide a contemporary update on the ‘ins and outs’ of membrane transport proteins implicated in osteoclast differentiation, function and bone homeostasis and discuss their therapeutic potential for the treatment of metabolic bone diseases.

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LncRNA, Important Player in Bone Development and Disease

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666190904161707 ◽

2020 ◽

Vol 20 (1) ◽

pp. 50-66 ◽

Cited By ~ 4

Author(s):

Dijie Li ◽

Chaofei Yang ◽

Chong Yin ◽

Fan Zhao ◽

Zhihao Chen ◽

...

Keyword(s):

Bone Disease ◽

Bone Cells ◽

Therapeutic Potential ◽

Bone Development ◽

Normal Function ◽

Bone Diseases ◽

Transcriptional Networks ◽

Bone Biology ◽

Protein Coding ◽

Wide Range

Background: Bone is an important tissue and its normal function requires tight coordination of transcriptional networks and signaling pathways, and many of these networks/ pathways are dysregulated in pathological conditions affecting cartilage and bones. Long non-coding RNA (lncRNA) refers to a class of RNAs with a length of more than 200 nucleotides, lack of protein-coding potential, and exhibiting a wide range of biological functions. Although studies on lcnRNAs are still in their infancy, they have emerged as critical players in bone biology and bone diseases. The functions and exact mechanism of bone-related lncRNAs have not been fully classified yet. Objective: The objective of this article is to summarize the current literature on lncRNAs on the basis of their role in bone biology and diseases, focusing on their emerging molecular mechanism, pathological implications and therapeutic potential. Discussion: A number of lncRNAs have been identified and shown to play important roles in multiple bone cells and bone disease. The function and mechanism of bone-related lncRNA remain to be elucidated. Conclusion: At present, majority of knowledge is limited to cellular levels and less is known on how lncRNAs could potentially control the development and homeostasis of bone. In the present review, we highlight some lncRNAs in the field of bone biology and bone disease. We also delineate some lncRNAs that might have deep impacts on understanding bone diseases and providing new therapeutic strategies to treat these diseases.

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