Senescent preosteoclast secretome promotes metabolic syndrome associated osteoarthritis through Cyclooxygenase 2

  1. Weiping Su
  2. Guanqiao Liu
  3. Bahram Mohajer
  4. Jiekang Wang
  5. Alena Shen
  6. Weixin Zhang
  7. Bin Liu
  8. Ali Guermazi
  9. Peisong Gao
  10. Xu Cao
  11. Shadpour Demehri  Is a corresponding author
  12. Mei Wan  Is a corresponding author
  1. Johns Hopkins University, United States
  2. University of Southern California, United States
  3. Boston University School of Medicine, United States

Abstract

Background: Metabolic syndrome–associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA.

Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system.

Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal anti-inflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA.

Conclusions: Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential.

Funding: This work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to M.W., R01AR079620 to S.D., and P01AG066603 to X.C.

Data availability

The data that support the findings of this study are available within the article and Supplementary file. Sequencing data have been deposited in Dryad and can be acquired through online portal at https://doi.org/10.5061/dryad.q2bvq83n6. The naming and version of OAI dataset files used in our study are listed in Supplementary file 1C and can be acquired through OAI online portal at https://nda.nih.gov/oai.

The following data sets were generated

Article and author information

Author details

  1. Weiping Su

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  2. Guanqiao Liu

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Bahram Mohajer

    Musculoskeletal Radiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Jiekang Wang

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Alena Shen

    Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  6. Weixin Zhang

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  7. Bin Liu

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Ali Guermazi

    Department of Radiology, Boston University School of Medicine, Boston, United States
    Competing interests
    Ali Guermazi, received consultancy fees from Pfizer, Novartis, MerckSerono, TissueGene, AstraZeneca, and Regeneron. The author has no other competing interests to declare..
  9. Peisong Gao

    Johns Hopkins Asthma & Allergy Center, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  10. Xu Cao

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8614-6059
  11. Shadpour Demehri

    Musculoskeletal Radiology, Johns Hopkins University, Baltimore, United States
    For correspondence
    sdemehr1@jh.edu
    Competing interests
    No competing interests declared.
  12. Mei Wan

    Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, United States
    For correspondence
    mwan4@jhmi.edu
    Competing interests
    Mei Wan, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9404-540X

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: We used data from the longitudinal multi-center OAI study (2004-2015 clinicaltrials.gov identifier: NCT00080171). All 4,796 enrolled patients gave written informed consent. Institutional review boards of four OAI collaborating centers have approved the OAI study's Health Insurance Portability and Accountability Act-compliant protocol (approval number: FWA00000068).

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Version history

  1. Received: April 27, 2022
  2. Preprint posted: May 5, 2022 (view preprint)
  3. Accepted: May 6, 2022
  4. Accepted Manuscript published: July 26, 2022 (version 1)
  5. Version of Record published: August 10, 2022 (version 2)

Copyright

© 2022, Su et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Weiping Su
  2. Guanqiao Liu
  3. Bahram Mohajer
  4. Jiekang Wang
  5. Alena Shen
  6. Weixin Zhang
  7. Bin Liu
  8. Ali Guermazi
  9. Peisong Gao
  10. Xu Cao
  11. Shadpour Demehri
  12. Mei Wan
(2022)
Senescent preosteoclast secretome promotes metabolic syndrome associated osteoarthritis through Cyclooxygenase 2
eLife 11:e79773.
https://doi.org/10.7554/eLife.79773

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    Jeffrey Thompson, Yidi Wang ... Ulrich H von Andrian
    Research Article Updated

    Background:

    Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

    Methods:

    A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

    Results:

    A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

    Conclusions:

    Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

    Funding:

    This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).

    1. Medicine
    Runze Yang, Tianhao Xu ... Weili Fu
    Tools and Resources Updated

    Background:

    To systematically identify cell types in the human ligament, investigate how ligamental cell identities, functions, and interactions participated in the process of ligamental degeneration, and explore the changes of ligamental microenvironment homeostasis in the disease progression.

    Methods:

    Using single-cell RNA sequencing and spatial RNA sequencing of approximately 49,356 cells, we created a comprehensive cell atlas of healthy and degenerated human anterior cruciate ligaments. We explored the variations of the cell subtypes’ spatial distributions and the different processes involved in the disease progression, linked them with the ligamental degeneration process using computational analysis, and verified findings with immunohistochemical and immunofluorescent staining.

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    This cell atlas provides the molecular foundation for investigating how ligamental cell identities, biochemical functions, and interactions contributed to the ligamental degeneration process. The discoveries revealed the pathogenesis of ligamental degeneration at the single-cell and spatial level, which is characterized by extracellular matrix remodeling. Our results provide new insights into the control of ligamental degeneration and potential clues to developing novel diagnostic and therapeutic strategies.

    Funding:

    This study was funded by the National Natural Science Foundation of China (81972123, 82172508, 82372490) and 1.3.5 Project for Disciplines of Excellence of West China Hospital Sichuan University (ZYJC21030, ZY2017301).