RANKL/OPG ratio regulates odontoclastogenesis in damaged dental pulp

Daisuke Nishida,Toshihide Mizoguchi,Yasuhiro Kobayashi,Akihiro Hosoya,Nobuyuki Udagawa,Yuko Nakamichi,Atsushi Arai,Mengyu Yang,Lijuan Zhao,Kanji Horibe

doi:10.1038/s41598-021-84354-y

Abstract

Bone-resorbing osteoclasts are regulated by the relative ratio of the differentiation factor, receptor activator NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). Dental tissue-localized-resorbing cells called odontoclasts have regulatory factors considered as identical to those of osteoclasts; however, it is still unclear whether the RANKL/OPG ratio is a key factor for odontoclast regulation in dental pulp. Here, we showed that odontoclast regulators, macrophage colony-stimulating factor-1, RANKL, and OPG were detectable in mouse pulp of molars, but OPG was dominantly expressed. High OPG expression was expected to have a negative regulatory effect on odontoclastogenesis; however, odontoclasts were not detected in the dental pulp of OPG-deficient (KO) mice. In contrast, damage induced odontoclast-like cells were seen in wild-type pulp tissues, with their number significantly increased in OPG-KO mice. Relative ratio of RANKL/OPG in the damaged pulp was significantly higher than in undamaged control pulp. Pulp damages enhanced hypoxia inducible factor-1α and -2α, reported to increase RANKL or decrease OPG. These results reveal that the relative ratio of RANKL/OPG is significant to pulpal odontoclastogenesis, and that OPG expression is not required for maintenance of pulp homeostasis, but protects pulp from odontoclastogenesis caused by damages.

Highlights

Bone-resorbing osteoclasts are regulated by the relative ratio of the differentiation factor, receptor activator NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG)
The relative ratio of Rankl to Opg in molars was significantly lower than that in femora in both normalized conditions using glyceraldehyde 3-phosphate dehydrogenase (Gapdh) or Col1a1 (Fig. 1E). These results suggest that the odontoclast inducible factors, colony-stimulating factor-1 (CSF-1) and RANKL are detectable in the healthy dental pulp, but high expression of OPG may be a negative regulator of odontoclastogenesis
We examined the significance of OPG expression in the normal dental pulp environment using OPG-KO mice, and demonstrated that the features of OPG-deficient pulp tissues were comparable to those in wild-type control mice

Summary

Introduction

Bone-resorbing osteoclasts are regulated by the relative ratio of the differentiation factor, receptor activator NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). Osteoclast differentiation factors, macrophage colony-stimulating factor-1 (CSF-1) and receptor activator of nuclear factor kappa-Β ligand (RANKL), are expressed by bone-forming cells such as osteoblasts and o steocytes[5,6]. CSF-1 is expressed in the pulp tissues, and contributes to the proliferation of resident macrophages[19] These reports suggest that the essential factors for odontoclast differentiation are expressed in the pulp environment. HIF-2α upregulates RANKL in osteoblastic cells[25] or fibroblast-like synoviocytes[26]; the effects of traumatic dental tissue damages on odontoclast regulating factors expressed in the pulp environment remain unclear. It is well known that OPG-knockout (KO) mice exhibit severe osteoporosis due to increased osteoclastogenesis in bone tissues[28,29]; the phenotypes in healthy or damaged dental pulp tissues of these mice have not been investigated

Methods

Results

Conclusion