PDGFR in PDGF-BB/PDGFR Signaling Pathway Does Orchestrates Osteogenesis in a Temporal Manner

Fangqian Wang; Yuxiao Ye; Zengjie Zhang; Wangsiyuan Teng; Hangxiang Sun; Xupeng Chai; Xingzhi Zhou; Jiayu Chen; Haochen Mou; Yinwang Eloy; Xiaoqiang Jin; Liang Chen; Zhenxuan Shao; Yan Wu; Yue Shen; An Liu; Peng Lin; Jianwei Wang; Xiaohua Yu; Zhaoming Ye

doi:10.34133/research.0086

PDGFR in PDGF-BB/PDGFR Signaling Pathway Does Orchestrates Osteogenesis in a Temporal Manner

Research (Wash D C). 2023 May 5:6:0086. doi: 10.34133/research.0086. eCollection 2023.

Authors

Fangqian Wang^{1

2

3}, Yuxiao Ye⁴, Zengjie Zhang^{1

2

3}, Wangsiyuan Teng^{1

2

3}, Hangxiang Sun^{1

2

3}, Xupeng Chai^{1

2

3}, Xingzhi Zhou^{1

2

3}, Jiayu Chen^{1

2

3}, Haochen Mou^{1

2

3}, Yinwang Eloy^{1

2

3}, Xiaoqiang Jin^{1

2

3}, Liang Chen^{1

2

3}, Zhenxuan Shao^{1

2

3}, Yan Wu^{1

2

3}, Yue Shen^{1

2

3}, An Liu^{1

2

3}, Peng Lin^{1

2

3}, Jianwei Wang^{1

2

3}, Xiaohua Yu^{1

2

3}, Zhaoming Ye^{1

2

3}

Affiliations

¹ Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China.
² Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China.
³ Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
⁴ School of Material Science and Engineering, University of New South Wales, Sydney 2052, Australia.

Abstract

Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor-β (PDGFR-β) pathway is conventionally considered as an important pathway to promote osteogenesis; however, recent study suggested its role during osteogenesis to be controversial. Regarding the differential functions of this pathway during 3 stages of bone healing, we hypothesized that temporal inhibition of PDGF-BB/PDGFR-β pathway could shift the proliferation/differentiation balance of skeletal stem and progenitor cells, toward osteogenic lineage, which leads to improved bone regeneration. We first validated that inhibition of PDGFR-β at late stage of osteogenic induction effectively enhanced differentiation toward osteoblasts. This effect was also replicated in vivo by showing accelerated bone formation when block PDGFR-β pathway at late stage of critical bone defect healing mediated using biomaterials. Further, we found that such PDGFR-β inhibitor-initiated bone healing was also effective in the absence of scaffold implantation when administrated intraperitoneally. Mechanistically, timely inhibition of PDGFR-β blocked extracellular regulated protein kinase 1/2 pathway, which shift proliferation/differentiation balance of skeletal stem and progenitor cell to osteogenic lineage by upregulating osteogenesis-related products of Smad to induce osteogenesis. This study offered updated understanding of the use of PDGFR-β pathway and provides new insight routes of action and novel therapeutic methods in the field of bone repair.