Bone-targeted bortezomib increases bone formation within Calvarial trans-sutural distraction osteogenesis

Hongyu Chen; Guanhui Cai; Xiaolei Ruan; Yahui Lu; Gen Li; Zhenwei Chen; Zhaolan Guan; Hengwei Zhang; Wen Sun; Hua Wang

doi:10.1016/j.bone.2023.116677

Bone-targeted bortezomib increases bone formation within Calvarial trans-sutural distraction osteogenesis

Bone. 2023 Apr:169:116677. doi: 10.1016/j.bone.2023.116677. Epub 2023 Jan 13.

Authors

Hongyu Chen¹, Guanhui Cai¹, Xiaolei Ruan¹, Yahui Lu¹, Gen Li¹, Zhenwei Chen¹, Zhaolan Guan¹, Hengwei Zhang², Wen Sun³, Hua Wang⁴

Affiliations

¹ Jiangsu Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
² Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
³ Jiangsu Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. Electronic address: wensun@njmu.edu.cn.
⁴ Jiangsu Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. Electronic address: huawang@njmu.edu.cn.

PMID: 36646264
DOI: 10.1016/j.bone.2023.116677

Abstract

The high rate of relapse in craniofacial disharmony treatment via trans-sutural distraction osteogenesis (TSDO) is due to the failure to form a stable bone bridge in the suture gap. Bisphosphonates (BP) have a high propensity to localize to hydroxyapatite in the bone matrix and are commonly used as targeting ligands for local delivery of therapeutics into bone microenvironment. Bone-targeted Bortezomib (BP-Btz) is chemosynthetic by linking Btz (Bortezomib) to a BP residue and could target bone tissue to promote osteoblast differentiation and inhibit osteoclastogenesis. Here, suture-derived mesenchymal stem cells (SuSCs) and osteoclasts were treated with Btz and BP-Btz. Aforesaid drugs were injected locally into the sagittal sutures to explore their effects in TSDO. Further, pharmacological properties of BP-Btz in the suture expansion model were assessed by fluorescent BP analogs and levels of total ubiquitinated (Ub)-proteins. The results showed that BP-Btz could stimulate osteogenic differentiation of SuSCs, bind to bone matrix and inhibit osteoclastogenesis. Biological effects of BP-Btz were similar with those of Btz in osteoblast differentiation and osteoclastogenesis inhibition in vitro. Activated bone metabolism were detected after 14 days in the sagittal suture expansion model. Increased osteoid area, remarkably decreased osteoclast surface and enhanced osteogenesis were detected in vivo after treatment with BP-Btz. Green fluorescence signal detection and pharmacodynamic studies revealed that BP-Btz bound to suture edge, released Btz in remodeling conditions, had a higher local concentration and sustained longer than free Btz. This study delineated the clinical potential of bone-targeted Btz conjugate as an efficacious strategy to promote trans-sutural distraction osteogenesis.

Keywords: Bisphosphonates; Bone volume; Bone-targeted bortezomib; Osteoblast differentiation; Trans-sutural distraction osteogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone and Bones
Bortezomib / pharmacology
Cranial Sutures
Osteogenesis*
Osteogenesis, Distraction* / methods

Substances

Bortezomib