PDGF-BB exhibited therapeutic effects on rat model of bisphosphonate-related osteonecrosis of the jaw by enhancing angiogenesis and osteogenesis

Gao, Si-yong; Lin, Rui-bang; Huang, Si-hui; Liang, Yu-jie; Li, Xiang; Zhang, Si-en; Ouyang, Dai-qiao; Li, Kan; Zheng, Guang-sen; Liao, Gui-qing

Affiliations

¹Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory, Sun Yat-Sen University, Guangzhou, China

Abstract and keywords

The mechanism and effective treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) are still uncertain. Our previous study revealed that zoledronate (ZOL) preferentially inhibited osteoclasts formation and platelet-derived growth factor-BB (PDGF-BB) secretion, causing suppression of angiogenesis and osteogenesis in vitro. The present study aimed to elucidate whether PDGF-BB had therapeutic effects on rat model of BRONJ by enhancing angiogenesis and angiogenesis. Firstly, rat model of BRONJ was established by ZOL and dexamethasone administration, followed by teeth extraction. The occurrence of BRONJ was confirmed and detected dead bone formation by maxillae examination, micro-CT scan and HE staining (10/10). Compared to control rats (0/10), both angiogenesis and mature bone formation were suppressed in BRONJ-like rats, evidenced by enzyme-linked immunosorbent assay (ELISA) for VEGF (P < 0.01), immunohistochemistry of CD31 (P < 0.05) and OCN (P < 0.01). Moreover, in the early stage of bone healing, the number of preosteoclasts (P < 0.001) and PDGF-BB secretion (P < 0.05) were significantly decreased in bisphosphonates-treated rats, along with the declined numbers of microvessels (P < 0.05) and osteoblasts (P < 0.05). In vitro study, CCK8 assay, alizarin red S staining and western blot assay showed that mandible-derived bone marrow mesenchymal stem cells (BMMSCs) in BRONJ-like rats presented suppressed functions of proliferation, osteogenesis and angiogenesis. Interestingly, recombinant PDGF-BB was able to rescue the impaired functions of BMMSCs derived from BRONJ-like rats at more than 10 ng/ml. Then fibrin sealant with or without recombinant PDGF-BB were tamped into the socket after debridement in BRONJ rats. After 8 weeks, fibrin sealant containing PDGF-BB showed significant therapeutic effects on BRONJ-like rats (bone healing: 8/10 vs 3/10, P < 0.05) with enhancing microvessels and mature bone formation. Our study suggested that the inhibition of angiogenesis and osteogenesis, the potential mechanisms of BRONJ, might partly result from suppression of PDGF-BB secretion in the early stage of bone healing. PDGF-BB local treatment after debridement might avail the healing of BRONJ by increasing angiogenesis and osteogenesis.

Keywords: Platelet derived growth factor-BB; Bisphosphonate-related osteonecrosis of the jaw; Mesenchymal stem cells; Angiogenesis; Osteogenesis; Treatment

Links

DOI: 10.1016/j.bone.2019.115117

PubMed: 31676407

WoS: 000615747700008

History

Received: 2019-08-13

Revised: 2019-10-21

Accepted: 2019-10-21

Online: 2019-10-30

Cited Works (3)

Year	Entry
2014	Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. March 20, 2014;507(7492):323-328.
2003	Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. September 2003;61(9):1115-1117.
2011	Russell RGG. Bisphosphonates: the first 40 years. Bone. July 2011;49(1):2-19.

Cited By (1)

Year	Entry
2023	Cao H, Shi K, Long J, Liu Y, Li L, Ye T, Huang C, Lai Y, Bai X, Qin L, Wang X. PDGF-BB prevents destructive repair and promotes reparative osteogenesis of steroid-associated osteonecrosis of the femoral head in rabbits. Bone. February 2023;167:116645.