Inhibition of RANKL and Sema4D improves residual ridge resorption in mice

Meri Hisamoto,Toshihiko Iwanaga,Shunsuke Kimura,Kai Iwata,Atsuro Yokoyama

doi:10.1038/s41598-022-08016-3

Meri Hisamoto, Toshihiko Iwanaga + Show 3 more

Open Access

https://doi.org/10.1038/s41598-022-08016-3

Copy DOI

Journal: Scientific Reports	Publication Date: Mar 8, 2022
Citations: 3	License type: open-access

Affiliation: Hokkaido University, Keio University

Abstract

Residual ridge resorption (RRR) is a chronic and progressive bone resorption following tooth loss. It causes deterioration of the oral environments and leads to the pathogenesis of various systemic diseases. However, the molecular mechanisms and risk factors for RRR progression are still unclear and controversial. In this study, we developed a tooth extraction model using mice for analyzing long-term morphological and gene expression changes in the alveolar bone. We further applied ovariectomy to this model to elucidate the effects of osteoporosis on RRR progression. As a result, the alveolar bone loss was biphasic and consisted of rapid loss in the early stages and subsequently slow and sustained bone loss over a long period. Histological analysis indicated that ovariectomy prolonged the activation of osteoclasts in the alveolar bone. Furthermore, the expressions of Tnfsf11 and Sema4d kept increasing for a long time in OVX mice. Administration of neutralization antibodies for receptor activator of NF-κB ligand (RANKL) effectively suppressed RRR. Similarly, inhibition of Semaphorin 4D (Sema4D) also improved alveolar bone loss. This study demonstrated that reduced ovarian function may be a risk factor for RRR and that RANKL and Sema4D suppression are potential treatments.

Highlights

Residual ridge resorption (RRR) is a continuous, often lifelong, alveolar bone resorption occurring after tooth loss
RRR in humans is characterized by sustained loss of the mandible and maxillary bone mass for prolonged periods following tooth extraction
We examined the temporal distribution of osteoclasts during healing of the extraction sockets using enzymatic histochemistry of tartrate‐resistant acid phosphatase (TRAP), which demonstrated that osteoclasts increased around the extraction sockets immediately after teeth extractions (Fig. 3a)

Summary

Introduction

Residual ridge resorption (RRR) is a continuous, often lifelong, alveolar bone resorption occurring after tooth loss. Most of the currently available drugs for osteoporosis are bisphosphonates or anti-RANKL monoclonal antibody drugs These drugs inhibit osteoclastic bone resorption; they can sometimes, but not necessarily, induce drug-related osteonecrosis of the jaw (ARONJ) following tooth e xtraction[10,11]. Another type of drug promoting osteoblastic bone formation is parathyroid hormone (PTH). Intermittent administration of PTH can treat osteoporosis of long bones and vertebrae[12], and some studies have indicated that intermittent PTH therapy could increase the mineral density of the jawbone in animal m odels[13,14]. A Sost-specific antibody treatment, which promotes bone formation and inhibits bone resorption, was developed and used clinically. An animal study suggested that sclerostin inhibition increased the alveolar bone volume and architecture in rats with alveolar bone loss[15]

Objectives

Methods

Results

Conclusion