Targeting actin-bundling protein L-plastin as an anabolic therapy for bone loss

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Abstract

Targeting L-plastin suppresses bone resorption and promotes bone formation by disrupting preosteoclast fusion.

Abstract

The actin-bundling protein L-plastin (LPL) mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL knockout mice show increased bone mass and cortical thickness with more mononuclear tartrate-resistant acid phosphatase–positive cells, osteoblasts, CD31 ^hiEmcn ^hi endothelial vessels, and fewer multinuclear osteoclasts in the bone marrow and periosteum. LPL deletion impeded preosteoclasts fusion by inhibiting filopodia formation and increased the number of preosteoclasts, which release platelet-derived growth factor-BB to promote CD31 ^hiEmcn ^hi vessel growth and bone formation. LPL expression is regulated by the phosphatidylinositol 3-kinase/AKT/specific protein 1 axis in response to receptor activator of nuclear factor–κB ligand. Furthermore, we identified an LPL inhibitor, oroxylin A, that could maintain bone mass in ovariectomy-induced osteoporosis and accelerate bone fracture healing in mice. In conclusion, we showed that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.

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Most cited references 44

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Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone.

Anjali P. Kusumbe, Saravana K. Ramasamy, Ralf H. Adams (2014)

The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.

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Osteoporosis

Juliet Compston, Michael McClung, William D Leslie (2019)

Fractures resulting from osteoporosis become increasingly common in women after age 55 years and men after age 65 years, resulting in substantial bone-associated morbidities, and increased mortality and health-care costs. Research advances have led to a more accurate assessment of fracture risk and have increased the range of therapeutic options available to prevent fractures. Fracture risk algorithms that combine clinical risk factors and bone mineral density are now widely used in clinical practice to target high-risk individuals for treatment. The discovery of key pathways regulating bone resorption and formation has identified new approaches to treatment with distinctive mechanisms of action. Osteoporosis is a chronic condition and long-term, sometimes lifelong, management is required. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. In people at a very high or imminent risk of fracture, therapy with teriparatide or abaloparatide should be considered; however, since treatment duration with these drugs is restricted to 18-24 months, treatment should be continued with an antiresorptive drug. Individuals at high risk of fractures do not receive adequate treatment and strategies to address this treatment gap-eg, widespread implementation of Fracture Liaison Services and improvement of adherence to therapy-are important challenges for the future.

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The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.

Nicole C. Wright, Anne C Looker, Kenneth Saag … (2014)

The goal of our study was to estimate the prevalence of osteoporosis and low bone mass based on bone mineral density (BMD) at the femoral neck and the lumbar spine in adults 50 years and older in the United States (US). We applied prevalence estimates of osteoporosis or low bone mass at the femoral neck or lumbar spine (adjusted by age, sex, and race/ethnicity to the 2010 Census) for the noninstitutionalized population aged 50 years and older from the National Health and Nutrition Examination Survey 2005-2010 to 2010 US Census population counts to determine the total number of older US residents with osteoporosis and low bone mass. There were more than 99 million adults aged 50 years and older in the US in 2010. Based on an overall 10.3% prevalence of osteoporosis, we estimated that in 2010, 10.2 million older adults had osteoporosis. The overall low bone mass prevalence was 43.9%, from which we estimated that 43.4 million older adults had low bone mass. We estimated that 7.7 million non-Hispanic white, 0.5 million non-Hispanic black, and 0.6 million Mexican American adults had osteoporosis, and another 33.8, 2.9, and 2.0 million had low bone mass, respectively. When combined, osteoporosis and low bone mass at the femoral neck or lumbar spine affected an estimated 53.6 million older US adults in 2010. Although most of the individuals with osteoporosis or low bone mass were non-Hispanic white women, a substantial number of men and women from other racial/ethnic groups also had osteoporotic BMD or low bone mass. © 2014 American Society for Bone and Mineral Research.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: November 2020

Publication date (Electronic): 18 November 2020

Volume: 6

Issue: 47

Electronic Location Identifier: eabb7135

Affiliations

[1 ]Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.

[2 ]Department of Orthopedics, No. 929 Hospital, Naval Medical University, Shanghai 200433, China.

[3 ]Graduate Management Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.

[4 ]Institute of translational medicine, Shanghai University, Shanghai 201900, China.

[5 ]Department of Pharmacy, Shanghai Ninth People’s Hospital, School of Medicine of Shanghai Jiao Tong University, Shanghai 201999, China.

[6 ]School of Pharmacy, Naval Medical University, Shanghai 200433, China.

[7 ]Central Laboratory, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.

[8 ]Department of Orthopedics, Shanghai Baoshan Luodian Hospital, Shanghai 201900, China.

[9 ]Department of Chemistry, Fudan University, Shanghai 200433, China.

Author notes

[*]

These authors contributed equally to this work.

[†]

Present address: School of Pharmacy, Naval Medical University, 325 Guohe Road, Yangpu District, Shanghai 200433, China.

[‡]

Present address: Department of Orthopedics, Shanghai Changhai Hospital, Naval Medical University, 168 Changhai Road, Yangpu District, Shanghai 200433, China.

[§ ]Corresponding author. Email: xfchen2010@ 123456163.com (X.F.C.); sirchenxiao@ 123456126.com (X.C.); drsujiacan@ 123456163.com (J.C.S.)

Author information

Xiaoqun Li http://orcid.org/0000-0001-9176-090X

Lipeng Wang http://orcid.org/0000-0001-8905-1944

Biaotong Huang http://orcid.org/0000-0001-8721-157X

Yanqiu Gu http://orcid.org/0000-0002-0280-6062

Yan Hu http://orcid.org/0000-0002-9484-6546

Jin Cui http://orcid.org/0000-0001-7910-6390

Qirong Zhou http://orcid.org/0000-0003-0858-6117

Xiaofei Chen http://orcid.org/0000-0002-6252-5879

Xiao Chen http://orcid.org/0000-0003-4517-0508

Jiacan Su http://orcid.org/0000-0001-7080-263X

Article

Publisher ID: abb7135

DOI: 10.1126/sciadv.abb7135

PMC ID: 7673802

PubMed ID: 33208358

SO-VID: c44de6b6-ba09-48f8-8d8b-6fdc935cfcc8

Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 12 March 2020

Date accepted : 01 October 2020