The elucidation of the key players of the Wnt-signaling pathway that results in bone formation opens avenues to specifically interfere with bone formation. Importantly, under normal circumstances, alveolar bone osteocytes express the inhibitor of Wnt- signaling, sclerostin, transcribed from the SOST gene [
31]. Sclerostin binds to the extracellular domain of LRP5/6 blocking the formation of the LRP/Wnt/Frizzled complex [
32], therefore inhibiting the canonical Wnt-signaling pathway, which has a crucial role in the differentiation and activation of osteoblasts [
19,
20]. Additionally, sclerostin exerts a catabolic effect on bone via the modulation RANKL/OPG ratio in osteocytes [
22,
33], although the specific pathway has yet to be defined. Strategies to neutralize sclerostin, for instance with clinically tested romosozumab, an anti-sclerostin antibody, hold promise for treatment of osteoporosis [
25]. Within periodontal tissues, sclerostin is expressed in osteocytes as well as cementocytes [
34]. The sclerostin knockout mouse exhibits a mild periodontal phenotype, with no alterations in teeth and a smaller periodontal ligament width due to enlarged cellular cementum [
35]. When inducing periodontitis, the sclerostin knockout mice were slightly protected compared to wild-type mice [
36]. Knockout of periostin, a structural component of the periodontium, leads to periodontitis due to structural anatomical deviation [
37]. These mice were treated with either a viral construct knocking down sclerostin or with a sclerostin neutralizing antibody. Knockdown of sclerostin not only restored alveolar bone height, but also improved the disorganized orientation of the periodontal ligament in these mice [
26••]. Similar results were obtained in a periodontitis rat model, using silk sutures around molar to induce periodontitis. These rats developed periodontitis within 4 weeks and after removal of the silk sutures, animals were treated with an antibody against sclerostin. Alveolar bone quality improved and original alveolar loss recovered in the treated group [
27•]. Locally administered sclerostin antibody induced limited regeneration of the alveolar bone but this lower effect was attributed to the inability to introduce a sufficient concentration of the antibody. It is theorized that more sophisticated methods of drug delivery to the alveolar bone would increase the efficacy of local treatment in periodontitis [
27•]. Independently, Chen et al. showed that treatment of periodontitis-induced rats with sclerostin antibody protected alveolar bone and increased the expression of osteoprotegerin (OPG) [
28]. One of the risk factors for using anti-resorptive treatment using either bisphosphonates or anti-RANKL antibody denosumab is osteonecrosis of the jaw [
38]. In a study comparing the clinically relevant doses of the sclerostin antibody with bisphosphonates in an experimental periodontitis rat model after ovariectomy, no osteonecrosis developed and also less alveolar bone was lost [
39]. Furthermore, all bone anabolic parameters improved after sclerostin antibody treatment [
39]. Progressive periodontitis eventually leads to tooth loss, hereby solving the chronic inflammation. Lost teeth can be replaced by implants, which can only be placed when the jawbone has enough height. Liu et al. have administered antibodies to sclerostin in edentulous rats. Rats with extracted teeth that received anti-sclerostin developed a thicker maxillary alveolar ridge height [
40]. Since anti-sclerostin improves the periodontal status and RANKL expressed by osteocytes causes periodontitis, it could be that sclerostin influences RANKL and thereby the catabolic nature of osteocytes. This was tested on the MLO-Y-4 cell line that expressed more RANKL when treated with increasing concentrations of sclerostin. Also, sclerostin treated MLO-Y4 cells gave rise to more osteoclasts in osteoclastogenesis assays that were more actively resorbing [
22]. Vice versa, osteoclasts may influence the expression of sclerostin in osteocytes. An Opg −/− mouse model was used to study coupling, the relationship between bone formation and bone degradation. Here, conditioned medium from osteoclasts lowered sclerostin expression in osteocytes. Anti-resorptive agents and anti-RANKL-induced sclerostin [
33].