Locally Secreted Semaphorin 4D Is Engaged in Both Pathogenic Bone Resorption and Retarded Bone Regeneration in a Ligature-Induced Mouse Model of Periodontitis

Abstract

It is well known that Semaphorin 4D (Sema4D) inhibits IGF-1-mediated osteogenesis by binding with PlexinB1 expressed on osteoblasts. However, its elevated level in the gingival crevice fluid of periodontitis patients and the broader scope of its activities in the context of potential upregulation of osteoclast-mediated periodontal bone-resorption suggest the need for further investigation of this multifaceted molecule. In short, the pathophysiological role of Sema4D in periodontitis requires further study. Accordingly, attachment of the ligature to the maxillary molar of mice for 7 days induced alveolar bone-resorption accompanied by locally elevated, soluble Sema4D (sSema4D), TNF-α and RANKL. Removal of the ligature induced spontaneous bone regeneration during the following 14 days, which was significantly promoted by anti-Sema4D-mAb administration. Anti-Sema4D-mAb was also suppressed in vitro osteoclastogenesis and pit formation by RANKL-stimulated BMMCs. While anti-Sema4D-mAb downmodulated the bone-resorption induced in mouse periodontitis, it neither affected local production of TNF-α and RANKL nor systemic skeletal bone remodeling. RANKL-induced osteoclastogenesis and resorptive activity were also suppressed by blocking of CD72, but not Plexin B2, suggesting that sSema4D released by osteoclasts promotes osteoclastogenesis via ligation to CD72 receptor. Overall, our data indicated that ssSema4D released by osteoclasts may play a dual function by decreasing bone formation, while upregulating bone-resorption.

IRAK4 inhibition: an effective strategy for immunomodulating peri-implant osseointegration via reciprocally-shifted polarization in the monocyte-macrophage lineage cells

“…Although an excess of osteoclastogenesis will lead to an inhibited effect on osteogenesis due to Scl and Sema 4D [42,43], CTHRC1 and BMP6 were con rmed to promote osteogenic differentiation [44,45]. In this study, the conditioned medium from osteoclasts did promote osteogenic differentiation and mineralization of BMSCs.…”

Single-cell Transcriptional Analysis of the Cellular Immune Response in the Oral Mucosa of Mice

“…1). Other groups have utilized similar periodontal resolution models in mice and evaluated the extent of healing 27,28 . Using this resolution model, Wong, et al showed gains in bone levels and decreased osteoclast quantity by 1 week following ligature removal and a near complete return to baseline levels by 2 weeks after ligature removal 28 .…”

Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis

“…For the induction of periodontal disease in C57BL6/J mice (6–8 weeks old; male n = 5/group), the maxillary second molar was ligatured with 5-0 silk, following the previously published protocol [ 43 , 44 ]. An anti-vimentin monoclonal antibody (5 μg/site, clone: 3CB2, mouse IgM) or isotype control IgM mAb (5 μg/site, clone: TEPC183, mouse IgM) was locally injected into the gingival tissue of a ligature-attached site every 2 days (day 0, 2, 4 and 6).…”

“…Resected maxillae were mechanically removed and exposed to 3% hydrogen peroxide overnight to remove all soft tissue. To evaluate the periodontal bone resorption, the distances from the cement–enamel junction to the alveolar bone crest on the buccal side of each root were measured for the maxillary second molar under the microscope, following the previously published protocol [ 43 , 44 ].…”