Osteocyte β1 integrin loss causes low bone mass and impairs bone mechanotransduction in mice

Lei Qin; Tailin He; Dazhi Yang; Yishu Wang; Zhenjian Li; Qinnan Yan; Peijun Zhang; Zecai Chen; Sixiong Lin; Huanqing Gao; Qing Yao; Zhen Xu; Bin Tang; Weihong Yi; Guozhi Xiao

doi:10.1016/j.jot.2022.03.008

Osteocyte β1 integrin loss causes low bone mass and impairs bone mechanotransduction in mice

J Orthop Translat. 2022 May 17:34:60-72. doi: 10.1016/j.jot.2022.03.008. eCollection 2022 May.

Authors

Lei Qin¹, Tailin He², Dazhi Yang¹, Yishu Wang², Zhenjian Li³, Qinnan Yan², Peijun Zhang², Zecai Chen¹, Sixiong Lin^{2

4}, Huanqing Gao², Qing Yao², Zhen Xu¹, Bin Tang³, Weihong Yi¹, Guozhi Xiao²

Affiliations

¹ Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, China.
² Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China.
³ Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China.
⁴ Department of Spine Surgery, Orthopedic Research Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, China.

Abstract

Background: The key focal adhesion protein β1 integrin plays an essential role in early skeletal development. However, roles of β1 integrin expression in osteocytes during the regulation of bone homeostasis and mechanotransduction are incompletely understood.

Materials and methods: To study the in vivo function of osteocyte β1 integrin in bone, we utilized the 10-kb Dmp1 (Dentin matrix acidic phosphoprotein 1)-Cre to generate mice with β1 integrin deletion in this cell type. Micro-computerized tomography, bone histomorphometry and immunohistochemistry were performed to determine the effects of osteocyte β1 integrin loss on bone mass accrual and biomechanical properties. In vivo tibial loading model was applied to study the possible involvement of osteocyte β1 integrin in bone mechanotransduction.

Results: Loss of β1 integrin expression in osteocytes resulted in a severe low bone mass and impaired biomechanical properties in load-bearing long bones and spines, but not in non-weight-bearing calvariae, in mice. The loss of β1 integrin led to enlarged size of lacunar-canalicular system, abnormal cell morphology, and disorientated nuclei in osteocytes. Furthermore, β1 integrin loss caused shortening and disorientated collagen I fibers in long bones. Osteocyte β1 integrin loss did not impact the osteoclast activities, but significantly reduced the osteoblast bone formation rate and, in the meantime, enhanced the adipogenic differentiation of the bone marrow stromal cells in the bone microenvironment. In addition, tibial loading failed to accelerate the anabolic bone formation and improve collagen I fiber integrity in mutant mice.

Conclusions: Our studies demonstrate an essential role of osteocyte β1 integrin in regulating bone homeostasis and mechanotransduction. The transnational potential of this article : This study reveals the regulatory roles of osteocyte β1 integrin in vivo for the maintenance of bone mass accrual, biomechanical properties, extracellular matrix integrity as well as bone mechanobiology, which defines β1 integrin a potential therapeutic target for skeletal diseases, such as osteoporosis.

Keywords: Bone homeostasis; Collagen I; Mechanotransduction; Osteocyte; β1 integrin.