β-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation leading to the development of glucocorticoid-induced osteonecrosis of femoral head

  1. Institute of Orthopadics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
  2. Department of Orthopedic Surgery, Lihuili Hospital Affiliated to Ningbo University, Ningbo, Zhejiang 315041, China
  3. School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
  4. Department of Orthopedic Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China
  5. Faculty of Pharmaceutical Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a response from the authors (if available).

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Editors

  • Reviewing Editor
    Yaoting Ji
    Wuhan University, Wuhan, China
  • Senior Editor
    Mone Zaidi
    Icahn School of Medicine at Mount Sinai, New York, United States of America

Reviewer #1 (Public Review):

Summary:
The manuscript by Xia et al. investigated the mechanisms underlying Glucocorticoid-induced osteonecrosis of the femoral head (GONFH). The authors observed that abnormal osteogenesis and adipogenesis are associated with decreased β-catenin in the necrotic femoral head of GONFH patients, and that the inhibition of β-catenin signalling leads to abnormal osteogenesis and adipogenesis in GONFH rats. Of interest, the deletion of β-catenin in Col2-expressing cells rather than in osx-expressing cells leads to a GONFH-like phenotype in the femoral head of mice.

Strengths:
A strength of the study is that it sets up a Col2-expressing cell-specific β-catenin knockout mouse model that mimics the full spectrum of osteonecrosis phenotype of GONFH. This is interesting and provides new insights into the understanding of GONFH. Overall, the data are solid and support their conclusions.

Reviewer #2 (Public Review):

Summary:
In this manuscript, the authors reported a study to uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of Glucocorticoid-induced osteonecrosis of the femoral head (GONFH). In this study, they first observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients, but the exact pathological mechanisms of GONFH remain unknown. They then performed in vivo and in vitro studies to further reveal that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation bone marrow stromal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats, and specific deletion of β-catenin in Col2+ cells shifted BMSCs commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice.

Strengths:
This innovative study provides strong evidence supporting that β-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation that contributes to the development of GONFH. This study also identifies an ideal genetically modified mouse model of GONFH. Overall, the experiment is logically designed, the figures are clear, and the data generated from humans and animals is abundant supporting their conclusions.

Weaknesses:
There is a lack of discussion to explain how the Wnt agonist 1 works. There are several types of Wnt ligands. It is not clear if this agonist only targets Wnt1 or other Wnts as well. Also, why Wnt agonist 1 couldn't rescue the GONFH-like phenotype in β-cateninCol2ER mice needs to be discussed.

Reviewer #3 (Public Review):

Summary:
In this manuscript, the authors are trying to delineate the mechanism underlying the osteonecrosis of the femoral head.

Strengths:
The authors provided compelling in vivo and in vitro data to demonstrate Col2+ cells and Osx+ cells were differentially expressed in the femoral head. Moreover, inducible knockout of β-catenin in Col2+ cells but not Osx+ cells lead to a GONFH-like phenotype including fat accumulation, subchondral bone destruction, and femoral head collapse, indicating that imbalance of osteogenic/adipogenic differentiation of Col2+ cells plays an important role in GONFH pathogenesis. Therefore, this manuscript provided mechanistic insights into osteonecrosis as well as potential therapeutic targets for disease treatment.

Weaknesses:
However, additional in-depth discussion regarding the phenotype observed in mice is highly encouraged.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation