Sympathetic Neurostress Drives Osteoblastic Exosomal MiR‐21 Transfer to Disrupt Bone Homeostasis and Promote Osteopenia

Hu, Cheng‐Hu; Sui, Bing‐Dong; Liu, Jin; Dang, Lei; Chen, Ji; Zheng, Chenxi; Shi, Songtao; Zhao, Ning; Dang, Minyan; He, Xiaoning; Zhang, Li‐Qiang; Gao, Peng; Chen, Nan; Kuang, Huijuan; Chen, Kai; Xu, Xiaolin; Yu, Xiaorui; Zhang, Ge; Jin, Yan

doi:10.1002/smtd.202100763

Cited by 24 publications

(39 citation statements)

References 69 publications

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“…Notably, in a recent study, we have shown that sympathetic regulation of the skeleton is mediated through osteoblast-osteoclast miR-21 communication via exosomes, 22 but the core concept underlying sympathetic regulation of bone remains consistent with previous reports, i.e. osteoblastic response represents as crucial and dominant.…”

Section: Introductionsupporting

confidence: 88%

“…According to our previous reports, miR-21 deficiency affects the bone remodeling balance and preserves bone homeostasis against multiple extrinsic factors. 22 – 24 In this study, we further revealed that with only osteoclastic expression of miR-21, osteopenia developed under the ISO challenge (Fig. S2b, c ) due to stimulated osteoclastic bone resorption with remained bone formation or the osteoblastic parameters (Fig.…”

Section: Resultssupporting

confidence: 51%

“…Previously, we have screened and found miR-21 as the most prominent sympatho-adrenergic tone-responsive microRNA in bone, and that miR-21 primarily regulated osteoclastogenesis in vivo. 22 – 24 Here, upregulation of osteoclastic miR-21 was further confirmed after ISO injection, which, however, did not occur in the lack of β 2 AR (Fig. 1k ).…”

Section: Resultsmentioning

confidence: 66%

“… 17 – 20 Nevertheless, under the context of sympatho-adrenergic regulation, mechanistic understanding and therapeutic manipulation promise of osteoclastogenesis are underdetermined, with osteoblastic paracrine factors currently known to be responsible for coupling osteoclast formation. 7 , 9 , 21 , 22 To address the mechanistic and therapeutic research needs, we have previously focused on investigating the post-transcriptional regulator microRNAs, and we found miR-21 to be a candidate to promote osteoclastogenesis in vivo and a biomarker for human osteoporosis. 22 – 24 We have also established an osteoclast-selective delivery method carrying an agomir/antagomir of a specific microRNA by conjugating D-Asp 8 (an aspartate octapeptide) with lipid nanoparticles.…”

Section: Introductionmentioning

confidence: 99%

“… 7 , 9 , 21 , 22 To address the mechanistic and therapeutic research needs, we have previously focused on investigating the post-transcriptional regulator microRNAs, and we found miR-21 to be a candidate to promote osteoclastogenesis in vivo and a biomarker for human osteoporosis. 22 – 24 We have also established an osteoclast-selective delivery method carrying an agomir/antagomir of a specific microRNA by conjugating D-Asp 8 (an aspartate octapeptide) with lipid nanoparticles. 18 , 25 – 27 In fact, the nucleic acid therapeutics are a growing field for the long-lasting or even curative effects, the clinical translation of which depends on delivery technologies including the lipid nanoparticles.…”

Section: Introductionmentioning

confidence: 99%

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Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

et al. 2022

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Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the β2-adrenergic receptor (β2AR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.

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Section: Introductionsupporting

confidence: 88%

Section: Resultssupporting

confidence: 51%

Section: Resultsmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

et al. 2022

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Bioprinted Scaffold Remodels the Neuromodulatory Microenvironment for Enhancing Bone Regeneration

Guo

2023

Adv Funct Materials

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Herein, a 3D bioprinted scaffold is proposed, containing a calcitonin gene‐related peptide (CGRP) and the β‐adrenergic receptor blocker propranolol (PRN) as a new method to achieve effective repair of bone defects. By leveraging the neuromodulation mechanism of bone regeneration, CGRP and PRN loaded mesoporous silica nanoparticles are added into a hybrid bio‐ink, which initially contains gelatin methacrylate, Poly (ethylene glycol) diacrylate and bone marrow mesenchymal stem cells (BMSCs). Subsequently, the optimized bio‐ink is used for 3D bioprinting to create a composite scaffold with a pre‐designed micro‐nano hierarchical structure. The migration and tube formation of human umbilical vein endothelial cells (HUVECs) can be promoted by the scaffold, which is beneficial to the formation of a new capillary network during the bone repair process. With the release of CGRP from the scaffold, the secretion of neuropeptides by sensory nerves is simulated. Meanwhile, the release of PRN can inhibit the binding process of catecholamine to β‐adrenergic receptor, co‐promoting the osteogenic differentiation of BMSCs with CGRP and silicon ions, which will effectively enhance bone repair of a critical‐sized cranial defect in a rat model. In conclusion, this study provides a promising strategy for bone defect repair by understanding the neuromodulatory mechanisms during bone regeneration.

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Bone‐Targeted Exosomes: Strategies and Applications

Wang

Duan

Wang

et al. 2023

Adv Healthcare Materials

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As the global population ages, bone-related diseases have increasingly become a major social problem threatening human health. Exosomes, as natural cell products, have been used to treat bone-related diseases due to their superior biocompatibility, biological barrier penetration, and therapeutic effects. Moreover, the modified exosomes exhibit strong bone-targeting capabilities that may improve efficacy and avoid systemic side effects, demonstrating promising translational potential. However, a review of bone-targeted exosomes is still lacking. Thus, the recently developed exosomes for bone-targeting applications in this review are focused. The biogenesis and bone-targeting regulatory functions of exosomes, the constructive strategies of modified exosomes to improve bone-targeting, and their therapeutic effects for bone-related diseases are introduced. By summarizing developments and challenges in bone-targeted exosomes, It is striven to shed light on the selection of exosome constructive strategies for different bone diseases and highlight their translational potential for future clinical orthopedics.

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Sympathetic Neurostress Drives Osteoblastic Exosomal MiR‐21 Transfer to Disrupt Bone Homeostasis and Promote Osteopenia

Abstract: (2 of 16)www.advancedsciencenews.com www.small-methods.com MiR-21 Deficiency Retards ISO-Induced Osteopenia and Affects the Bone Remodeling BalanceNext, we investigated whether miR-21 indeed contributed to the sympatho-adrenergic regulation of bone. To investigate this

Cited by 24 publications

References 69 publications

Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

Bioprinted Scaffold Remodels the Neuromodulatory Microenvironment for Enhancing Bone Regeneration

Bone‐Targeted Exosomes: Strategies and Applications

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