Clodronate-Loaded Liposome Treatment Has Site-Specific Skeletal Effects

Abstract

Ineffective oral wound healing is detrimental to patients’ oral health–related quality of life. Delineating the cellular mechanisms involved in optimal healing will elicit better approaches to treating patients with compromised healing. Osteal macrophages have recently emerged as important positive regulators of bone turnover. The contributions of macrophages to long bone healing have been studied, but their role in oral osseous wound healing following tooth extraction is less clear. Clodronate-loaded liposomes were used as a tool to deplete macrophages in C57BL/6J mice and assess oral osseous bone fill after extraction. In addition to macrophage ablation, osteoclast ablation occurred. Interestingly, depletion of macrophages and osteoclasts via clodronate treatment had differential effects based on skeletal location. In the nonwounded tibiae, clodronate treatment significantly increased CD68+ cells and decreased F4/80+ cells in the marrow, which correlated with increased trabecular bone volume fraction after 7 and 14 d. Serum formation and resorptive markers P1NP and TRAcP 5b were decreased as were tibial TRAP+ osteoclasts. In healing extraction sockets, clodronate treatment increased extraction socket trabecular bone thickness at 14 d, which correlated with decreased TRAP+ osteoclasts and F4/80+ macrophages. Conversely, nonwounded maxillary interseptal bone was unaffected by clodronate treatment. Furthermore, the increase in extraction socket bone fill with clodronate was less than the large increase in trabecular bone observed in a nonwounded long bone. These data suggest a temporal and spatial specificity in the roles of macrophages and osteoclasts in normal turnover and healing.

High‐Strength and Injectable Supramolecular Hydrogel Self‐Assembled by Monomeric Nucleoside for Tooth‐Extraction Wound Healing

“…CD68 + cells are normally involved in inflammatory infiltration and positively modulate bone homeostasis. [ 34 ] The number of CD68 + cells in the NC and 2‐FA gel groups showed similar trends, that is, CD68 expression increased in the early postextraction stage and decreased after complete healing (Figure 9c,e). However, the 2‐FA gel group exhibited significantly higher CD68 activation at PED1 and PED3, and lower CD68 activation at PED21, compared to the NC group, which was consistent with the osteoclast activity results (Figure 9a,b).…”

“…As a means to promote bone remodeling and complete bone healing, some researchers have applied clodronate to the extraction sockets. [ 34 ] Clodronate has been observed to deplete macrophages, leading to an increase in the trabecular bone volume fraction, which in turn results from a decrease in TRAP + osteoclasts. Accordingly, 2‐FA was hypothesized to have a similar effect on the macrophage population, resulting in more complete healing.…”

Dual-Wavelength Photosensitive Nano-in-Micro Scaffold Regulates Innate and Adaptive Immune Responses for Osteogenesis

“…In addition, the effect of clodronate on osteoclasts may directly affect the bone regeneration of biomaterials. Although this scheme for depleting macrophages in vivo may create unpredictable interfering effects, the validity of studying macrophages using this scheme is widely recognized [56][57][58].…”

The Contribution of Macrophages in Old Mice to Periodontal Disease

“…Other strategies for macrophage depletion exist, including administration of clodronate liposomes or using the transgenic Mac Fas–induced apoptosis (MaFIA) mouse. However, each method lacks specificity in their targeted depletion and can similarly result in depletion of osteoclasts (McCubbrey et al 2017; Michalski et al 2019).…”