Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

McDonald, Michelle; Khoo, Weng Hua; Ng, Pei Ying; Xiao, Yue; Zamerli, Jad; Thatcher, Peter; Kyaw, Wunna; Pathmanandavel, Karrnan; Grootveld, Abigail K.; Moran, Imogen; Butt, Danyal; Nguyen, Akira; Corr, Alexander; Warren, Sean; Biro, Maté; Butterfield, Natalie C.; Guilfoyle, Siobhan E.; Komla‐Ebri, Davide; Dack, Michael R.G.; Dewhurst, Hannah; Logan, John G.; Li, Yongxiao; Mohanty, Sindhu T.; Byrne, Niall; Terry, Rachael; Simic, Marija K.; Chai, Ryan C.; Quinn, J; Youlten, Scott E.; Pettitt, Jessica A.; Abi–Hanna, David; Jain, Rohit; Weninger, Wolfgang; Lundberg, Mischa; Sun, Shuting; Ebetino, Frank H.; Timpson, Paul; Lee, Woei Ming; Baldock, Paul A.; Rogers, Michael J.; Brink, Robert; Williams, Graham R.; Bassett, J H Duncan; Kemp, John P.; Pavlos, Nathan J.; Croucher, Peter I.; Phan, Tri Giang

doi:10.1530/ey.18.5.12

Cited by 22 publications

(26 citation statements)

References 28 publications

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“…We found that overexpression of miR-1224-5p significantly reduced the expression of FAK, Rac1/2/3, Rac1/CDC42, and Rho-A, which are related to the cytoskeletal structure and important for the morphology and function of osteoclasts. Considering the recently discovered osteomorphs 36 , we suspect that miR-1224-5p may simultaneously affect the recycling of osteoclasts, but we have not been able to verify this supposition. ADCY2 inactivation effectively decreases osteoclast formation and function by inhibiting osteoclast-specific gene expression.…”

Section: Discussionmentioning

confidence: 75%

MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2

Xie

Xue

et al. 2022

Exp Mol Med

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MicroRNAs (miRNAs) broadly regulate normal biological functions of bone and the progression of fracture healing and osteoporosis. Recently, it has been reported that miR-1224-5p in fracture plasma is a potential therapy for osteogenesis. To investigate the roles of miR-1224-5p and the Rap1 signaling pathway in fracture healing and osteoporosis development and progression, we used BMMs, BMSCs, and skull osteoblast precursor cells for in vitro osteogenesis and osteoclastogenesis studies. Osteoblastogenesis and osteoclastogenesis were detected by ALP, ARS, and TRAP staining and bone slice resorption pit assays. The miR-1224-5p target gene was assessed by siRNA-mediated target gene knockdown and luciferase reporter assays. To explore the Rap1 pathway, we performed high-throughput sequencing, western blotting, RT-PCR, chromatin immunoprecipitation assays and immunohistochemical staining. In vivo, bone healing was judged by the cortical femoral defect, cranial bone defect and femoral fracture models. Progression of osteoporosis was evaluated by an ovariectomy model and an aged osteoporosis model. We discovered that the expression of miR-1224-5p was positively correlated with fracture healing progression. Moreover, in vitro, overexpression of miR-1224-5p slowed Rankl-induced osteoclast differentiation and promoted osteoblast differentiation via the Rap1-signaling pathway by targeting ADCY2. In addition, in vivo overexpression of miR-1224-5p significantly promoted fracture healing and ameliorated the progression of osteoporosis caused by estrogen deficiency or aging. Furthermore, knockdown of miRNA-1224-5p inhibited bone regeneration in mice and accelerated the progression of osteoporosis in elderly mice. Taken together, these results identify miR-1224-5p as a key bone osteogenic regulator, which may be a potential therapeutic target for osteoporosis and fracture nonunion.

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Section: Discussionmentioning

confidence: 75%

MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2

Xie

Xue

et al. 2022

Exp Mol Med

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“…With increasing research using high-resolution sequencing and imaging techniques, the development of OCs has been clarified both in vivo and in vitro. Recent studies have revealed that OCs are recycled by fusion and fission to maintain their dynamic bone resorption activity in vivo ( 40 ). Single-cell RNA-seq has indicated that the stages of RANKL-induced OC differentiation in vitro can be divided into MPs, the MP stage, the DC-like precursor stages, membrane raft assembly, the initiation of RNA metabolism, the terminal differentiation of pOCs, and the formation of mOCs according to the expression of specific gene markers ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Suppression of osteoclast multinucleation via a posttranscriptional regulation–based spatiotemporally selective delivery system

et al. 2022

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Redundancy of multinucleated mature osteoclasts, which results from the excessive fusion of mononucleated preosteoclasts (pOCs), leads to osteolytic diseases such as osteoporosis. Unfortunately, the currently available clinical drugs completely inhibit osteoclasts, thus interfering with normal physiological bone turnover. pOC-specific regulation may be more suitable for maintaining bone homeostasis. Here, circBBS9, a previously unidentified circular RNA, was found to exert regulatory effects via the circBBS9/miR-423-3p/Traf6 axis in pOCs. To overcome the long-standing challenge of spatiotemporal RNA delivery to cells, we constructed biomimetic nanoparticles to achieve the pOC-specific targeted delivery of circBBS9. pOC membranes (POCMs) were extracted to camouflage cationic polymer for RNA interference with circBBS9 (POCM-NPs@siRNA/shRNA circBBS9 ). POCM-NPs endowed the nanocarriers with improved stability, accurate pOC targeting, fusogenic uptake, and reactive oxygen species–responsive release. In summary, our findings may provide an alternative strategy for multinucleated cell–related diseases that involves restriction of mononucleated cell multinucleation through a spatiotemporally selective delivery system.

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“…Such in silico gene prioritization approaches are valuable in this study, and similar methods have recently been employed by others. (60,61) However, implementing these strategies requires significant computational, genetic, and epidemiologic expertise. The work herein has three important features.…”

Section: Discussionmentioning

confidence: 99%

Prioritization of Genes Relevant to Bone Fragility Through the Unbiased Integration of Aging Mouse Bone Transcriptomics and Human GWAS Analyses

Kaya

Schurman

Dole

et al. 2020

Journal of Bone and Mineral Research

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Identifying new genetic determinants of bone mineral density (BMD) and fracture promises to yield improved diagnostics and therapies for bone fragility. However, prioritizing candidate genes from genome‐wide screens can be challenging. To overcome this challenge, we prioritized mouse genes that are differentially expressed in aging mouse bone based on whether their human homolog is associated with human BMD and/or fracture. Unbiased RNA‐seq analysis of young and old male C57BL/6 mouse cortical bone identified 1499, 1685, and 5525 differentially expressed genes (DEGs) in 1, 2, and 2.5‐year‐old bone, relative to 2‐month‐old bone, respectively. Gene‐based scores for heel ultrasound bone mineral density (eBMD) and fracture were estimated using published genome‐wide association studies (GWAS) results of these traits in the UK Biobank. Enrichment analysis showed that mouse bone DEG sets for all three age groups, relative to young bone, are significantly enriched for eBMD, but only the oldest two DEG sets are enriched for fracture. Using gene‐based scores, this approach prioritizes among thousands of DEGs by a factor of 5‐ to 100‐fold, yielding 10 and 21 genes significantly associated with fracture in the two oldest groups of mouse DEGs. Though these genes were not the most differentially expressed, they included Sost, Lrp5, and others with well‐established functions in bone. Several others have, as yet, unknown roles in the skeleton. Therefore, this study accelerates identification of new genetic determinants of bone fragility by prioritizing a clinically relevant and experimentally tractable number of candidate genes for functional analysis. Finally, we provide a website (http://www.mouse2human.org) to enable other researchers to easily apply our strategy. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Abstract: Highlights d Osteoclasts fission into daughter cells called osteomorphs d Osteomorphs fuse and recycle back into osteoclasts d Osteomorph upregulated genes control bone structure and function in mice d Osteomorph upregulated genes are implicated in rare and common bone diseases in humans

Cited by 22 publications

References 28 publications

MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2

MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2

Suppression of osteoclast multinucleation via a posttranscriptional regulation–based spatiotemporally selective delivery system

Prioritization of Genes Relevant to Bone Fragility Through the Unbiased Integration of Aging Mouse Bone Transcriptomics and Human GWAS Analyses

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