Effects of IL‐34 and anti‐IL‐34 neutralizing mAb on alveolar bone loss in a ligature‐induced model of periodontitis

Abstract Macrophage colony‐stimulating factor (M‐CSF) and interleukin‐34 (IL‐34) are ligands for the colony‐stimulating factor‐1 receptor (CSF‐1r) expressed on the surface of monocyte/macrophage lineage cells. The importance of coordinated signaling between M‐CSF/receptor activator of the nuclear factor kappa‐Β ligand (RANKL) in physiological and pathological bone remodeling and alveolar bone loss in response to oral bacterial colonization is well established. However, our knowledge about the IL‐34/RANKL signaling in periodontal bone loss remains limited. Recently published cohort studies have demonstrated that the expression patterns of IL‐34 are dramatically elevated in gingival crevicular fluid collected from patients with periodontitis. Therefore, the present study aims to evaluate the effects of IL‐34 on osteoclastogenesis in vitro and in experimental ligature‐mediated model of periodontitis using male mice. Our initial in vitro study demonstrated increased RANKL‐induced osteoclastogenesis of IL‐34‐primed osteoclast precursors (OCPs) compared to M‐CSF‐primed OCPs. Using an experimental model of ligature‐mediated periodontitis, we further demonstrated elevated expression of IL‐34 in periodontal lesions. In contrast, M‐CSF levels were dramatically reduced in these periodontal lesions. Furthermore, local injections of mouse recombinant IL‐34 protein significantly elevated cathepsin K activity, increased the number of tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts and promoted alveolar bone loss in periodontitis lesions. In contrast, anti‐IL‐34 neutralizing monoclonal antibody significantly reduced the level of alveolar bone loss and the number of TRAP‐positive osteoclasts in periodontitis lesions. No beneficial effects of locally injected anti‐M‐CSF neutralizing antibody were observed in periodontal lesions. This study illustrates the role of IL‐34 in promoting alveolar bone loss in periodontal lesions and proposes the potential of anti‐IL34 monoclonal antibody (mAb)‐based therapeutic regimens to suppress alveolar bone loss in periodontitis lesions.