Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets

Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature aging process is the leading cause of hormone-related osteoporosis for postmenopausal women, while glucocorticoid-induced osteoporosis remains the most common in drug-induced osteoporosis. Other medications and medical conditions related to secondary osteoporosis include proton pump inhibitors, hypogonadism, selective serotonin receptor inhibitors, chemotherapies, and medroxyprogesterone acetate. This review is a summary of the cellular and molecular mechanisms of bone turnover, the pathophysiology of osteoporosis, and their treatment. Nuclear factor-κβ ligand (RANKL) appears to be the critical uncoupling factor that enhances osteoclastogenesis. In contrast, osteoprotegerin (OPG) is a RANKL antagonist secreted by osteoblast lineage cells. Estrogen promotes apoptosis of osteoclasts and inhibits osteoclastogenesis by stimulating the production of OPG and reducing osteoclast differentiation after suppression of IL-1 and TNF, and subsequent M-CSF, RANKL, and IL-6 release. It can also activate the Wnt signaling pathway to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts rather than adipocytes. Estrogen deficiency leads to the uncoupling of bone resorption and formation; therefore, resulting in greater bone loss. Excessive glucocorticoids increase PPAR-2 production, upregulate the expression of Dickkopf-1 (DKK1) in osteoblasts, and inhibit the Wnt signaling pathway, thus decreasing osteoblast differentiation. They promote osteoclast survival by enhancing RANKL expression and inhibiting OPG expression. Appropriate estrogen supplement and avoiding excessive glucocorticoid use are deemed the primary treatment for hormone-related and glucocorticoid-induced osteoporosis. Additionally, current pharmacological treatment includes bisphosphonates, teriparatide (PTH), and RANKL inhibitors (such as denosumab). However, many detailed cellular and molecular mechanisms underlying osteoporosis seem complicated and unexplored and warrant further investigation.

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“…Osteoclast-Evs regulate osteoblasts formation. MSC-Evs promote the recruitment and activation of macrophages [ 40 ].…”

Section: Cellular and Molecular Mechanisms Of Bone Turnover Among Ost...mentioning

confidence: 99%

Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview

Wang

Chen

2023

IJMS

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“…Extracellular vesicles (EVs), considered for a long time a way used by cells to discard unwanted materials, have now been definitively recognized as a central way for cell-to-cell communication and molecule exchange, both in eukaryotes and in prokaryotes, as well as for trans-kingdom communications [ 216 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 ], thus suggesting an ancient evolutionary origin of EVs.…”

Section: Role Of Rbps In Rna Sorting To Extracellular Vesiclesmentioning

confidence: 99%

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

Schiera

Schirò

Liegro

2022

IJMS

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A central aspect of nervous system development and function is the post-transcriptional regulation of mRNA fate, which implies time- and site-dependent translation, in response to cues originating from cell-to-cell crosstalk. Such events are fundamental for the establishment of brain cell asymmetry, as well as of long-lasting modifications of synapses (long-term potentiation: LTP), responsible for learning, memory, and higher cognitive functions. Post-transcriptional regulation is in turn dependent on RNA-binding proteins that, by recognizing and binding brief RNA sequences, base modifications, or secondary/tertiary structures, are able to control maturation, localization, stability, and translation of the transcripts. Notably, most RBPs contain intrinsically disordered regions (IDRs) that are thought to be involved in the formation of membrane-less structures, probably due to liquid–liquid phase separation (LLPS). Such structures are evidenced as a variety of granules that contain proteins and different classes of RNAs. The other side of the peculiar properties of IDRs is, however, that, under altered cellular conditions, they are also prone to form aggregates, as observed in neurodegeneration. Interestingly, RBPs, as part of both normal and aggregated complexes, are also able to enter extracellular vesicles (EVs), and in doing so, they can also reach cells other than those that produced them.

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“…Osteoimmunology focuses on the interaction between immune cells and the skeletal system [ 12 ]. Bone cells, such as osteoblasts, osteoclasts, osteocytes and immune cells like macrophages share the same micro-environment and a variety of molecules, working together within the concept of osteoimmunology [ 13 ]. Bone homeostasis is highly regulated with coordinated crosstalk among these cells [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Immune response is also critical in bone healing. Macrophage is a dynamic cell, derives from monocytes and participates in induction and resolution of metabolic/inflammation purposes [ 13 ]. Macrophages play pivotal and dynamic roles in bone regeneration, as monocyte migrates from the circulation to the local tissue.…”

Section: Introductionmentioning

confidence: 99%

“…Macrophages play pivotal and dynamic roles in bone regeneration, as monocyte migrates from the circulation to the local tissue. Monocyte differentiates into macrophage, and depending on the stimulus and microenvironment, polarizes into different types in vivo, including non-activated M0, classical or pro-inflammatory M1 and anti-inflammatory and pro-regenerative M2 [ 13 ]. Skeletal or osteal macrophages (osteomacs) have been reported to contribute to bone homeostasis and regeneration and to take part in an essential function, as remodeling [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Doped Electrospinned Material-Guides High Efficiency Regional Bone Regeneration

et al. 2023

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The main target of bone tissue engineering is to design biomaterials that support bone regeneration and vascularization. Nanostructured membranes of (MMA)1-co-(HEMA)1/(MA)3-co-(HEA)2 loaded with 5% wt of SiO2-nanoparticles (Si-M) were doped with zinc (Zn-Si-M) or doxycycline (Dox-Si-M). Critical bone defects were effectuated on six New Zealand-bred rabbit skulls and then they were covered with the membranes. After six weeks, a histological analysis (toluidine blue technique) was employed to determine bone cell population as osteoblasts, osteoclasts, osteocytes, M1 and M2 macrophages and vasculature. Membranes covering the bone defect determined a higher count of bone cells and blood vessels than in the sham group at the top regions of the defect. Pro-inflammatory M1 appeared in a higher number in the top regions than in the bottom regions, when Si-M and Dox-Si-M were used. Samples treated with Dox-Si-M showed a higher amount of anti-inflammatory and pro-regenerative M2 macrophages. The M1/M2 ratio obtained its lowest value in the absence of membranes. On the top regions, osteoblasts were more abundant when using Si-M and Zn-Si-M. Osteoclasts were equally distributed at the central and lateral regions. The sham group and samples treated with Zn-Si-M attained a higher number of osteocytes at the top regions. A preferential osteoconductive, osteoinductive and angiogenic clinical environment was created in the vicinity of the membrane placed on critical bone defects.

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Extracellular Vesicles in Bone Homeostasis: Emerging Mediators of Osteoimmune Interactions and Promising Therapeutic Targets

Cited by 17 publications

References 100 publications

Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview

Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

Doped Electrospinned Material-Guides High Efficiency Regional Bone Regeneration

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