The Antimicrobial Peptide, LL-37, Inhibitsin vitroOsteoclastogenesis

Abstract

Uncoupled bone resorption leads to net alveolar bone loss in periodontitis. The deficiency of LL-37, the only human antimicrobial peptide in the cathelicidin family, in patients with aggressive periodontitis suggests that LL-37 may play a pivotal role in the inhibition of alveolar bone destruction in periodontitis. We aimed to investigate a novel function of LL-37 in osteoimmunity by blocking osteoclastogenesis in vitro. Human osteoclast progenitor cells were isolated from a buffy coat of blood samples. The cells were cultured in the presence of various concentrations of LL-37 during an in vitro induction of osteoclastogenesis. Non-toxic doses of LL-37 could block multinuclear formation of the progenitor cells and significantly diminish the number of tartrate-resistant acid-phosphatase-positive cells and the formation of resorption pits (p < 0.05), whereas these concentrations induced cellular proliferation, as demonstrated by increased expression of proliferating cell nuclear antigen. Expression of several osteoclast genes was down-regulated by LL-37 treatment. It was demonstrated that nuclear translocation of nuclear-factor-activated T-cells 2 (NFAT2) was blocked by LL-37 treatment, consistent with a significant reduction in the calcineurin activity (p < 0.005). Collectively, our findings demonstrate that LL-37 inhibits the in vitro osteoclastogenesis by inhibiting the calcineurin activity, thus preventing nuclear translocation of NFAT2.

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

“…More recently, evidence has accumulated that the antiinfective effects of HDPs are also the result of their immunomodulatory properties such as upregulation of expression of chemokines that, in turn, recruit and activate host immune cells [6,14,15,19,28,38]. HDPs can also modulate production of pro-and antiinflammatory cytokines to control the inflammatory response [14,15,19,28,38] and can inhibit osteoclast differentiation [20,40] and thereby potentially can reduce inflammatory osteolysis and the lethal consequences of septic shock. As a result of their unique immunomodulatory mechanisms of action, HDPs are also less likely to induce bacterial resistance than are conventional antibiotics [14,15].…”

Roles of cathelicidin‐related antimicrobial peptide in murine osteoclastogenesis

“…CRAMP and LL-37 share 47% identity and 67% similarity in their amino acid sequences. Therefore, these observations raised the question of whether LL-37 and CRAMP have similar activities or have distinct activities, which might account for the different results obtained by us and by Supanchart et al 32 A candidate target for different actions of CRAMP/LL-37 was the P2X 7 purinergic receptor. LL-37 enhanced ATP-induced Ca 2+ influx mediated by the human P2X 7 receptor, 33 while CRAMP inhibited it mediated by the mouse P2X 7 receptor.…”

“…32 reported that LL-37 suppressed RANKL-induced osteoclastogenesis in human peripheral blood mononuclear cell (PBMC) cultures. CRAMP and LL-37 share 47% identity and 67% similarity in their amino acid sequences.…”

“…S2). In addition, Supanchart et al 32 showed that the neutralizing antibody against the human P2X 7 receptor failed to reverse the effect of LL-37 in human PBMC cultures. These results suggest that the P2X 7 receptor-mediated signalling is not involved in osteoclastogenesis in humans and mice.…”

Defensins defend against bone loss

“…Although the earlier studies were not entirely convincing, the idea was proposed that CRAMP and the human analog LL-37 could serve as an osteoblast-derived protector in bacterial infection-induced osteoclastic bone reabsorption [3,4]. In this issue of J Mol Med, Park and colleagues pursue this idea further by investigating humanβ-defensin-3 C-15 (HBD3) and any role that small peptide could have in inhibiting bone reabsorption by impairing osteoclast activity [5].…”