Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption,Cell

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Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
Cell ( IF 45.5 ) Pub Date : 2021-02-25 , DOI: 10.1016/j.cell.2021.02.002
Michelle M McDonald ₁ , Weng Hua Khoo ₁ , Pei Ying Ng ₂ , Ya Xiao ₃ , Jad Zamerli ₃ , Peter Thatcher ₃ , Wunna Kyaw ₄ , Karrnan Pathmanandavel ₄ , Abigail K Grootveld ₄ , Imogen Moran ₄ , Danyal Butt ₄ , Akira Nguyen ₄ , Alexander Corr ₁ , Sean Warren ₅ , Maté Biro ₆ , Natalie C Butterfield ₇ , Siobhan E Guilfoyle ₇ , Davide Komla-Ebri ₇ , Michael R G Dack ₇ , Hannah F Dewhurst ₇ , John G Logan ₇ , Yongxiao Li ₈ , Sindhu T Mohanty ₁ , Niall Byrne ₁ , Rachael L Terry ₁ , Marija K Simic ₁ , Ryan Chai ₃ , Julian M W Quinn ₁ , Scott E Youlten ₃ , Jessica A Pettitt ₃ , David Abi-Hanna ₁ , Rohit Jain ₉ , Wolfgang Weninger ₁₀ , Mischa Lundberg ₁₁ , Shuting Sun ₁₂ , Frank H Ebetino ₁₂ , Paul Timpson ₅ , Woei Ming Lee ₈ , Paul A Baldock ₁ , Michael J Rogers ₁ , Robert Brink ₁₃ , Graham R Williams ₇ , J H Duncan Bassett ₇ , John P Kemp ₁₄ , Nathan J Pavlos ₂ , Peter I Croucher ₁ , Tri Giang Phan ₁₃

Affiliation

Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.
Bone Biology & Disease Laboratory, School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia.
Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
Immunology Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
Cancer, Garvan Institute of Medical Research, Sydney, NSW, Australia.
EMBL Australia, Single Molecule Science Node, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.
John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Immune Imaging Program, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Immune Imaging Program, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Dermatology, Medical University of Vienna, Vienna, Austria.
The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia; Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, NSW, Australia.
Biovinc, Pasadena, CA, USA.
St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Immunology Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.

中文翻译：

在 RANKL 刺激的骨吸收过程中，破骨细胞通过骨形态进行回收

破骨细胞是由单核细胞/巨噬细胞衍生的前体细胞融合形成的大型多核骨吸收细胞，被认为一旦吸收完成就会发生细胞凋亡。在这里，通过活体成像，我们揭示了 RANKL 刺激的破骨细胞具有另一种细胞命运，其中它们分裂成称为骨形态的子细胞。抑制 RANKL 会阻碍这种细胞循环并导致骨形态积累。单细胞RNA测序表明，骨形态在转录上与破骨细胞和巨噬细胞不同，并表达许多非经典破骨细胞基因，这些基因在小鼠体内被删除时与结构和功能性骨表型相关。此外，人类骨形态基因直系同源物的遗传变异会导致单基因骨骼疾病，并与骨矿物质密度（一种多基因骨骼特征）相关。因此，破骨细胞通过骨形态进行回收，骨形态是一种参与骨吸收调节的细胞类型，可能是骨骼疾病治疗的目标。

更新日期：2021-03-04

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