Sclerostin antibody stimulates bone regeneration after experimental periodontitis

Abstract

The reconstruction of large osseous defects due to periodontitis is a challenge in regenerative therapy. Sclerostin, secreted by osteocytes, is a key physiological inhibitor of osteogenesis. Pharmacologic inhibition of sclerostin using sclerostin-neutralizing monoclonal antibody (Scl-Ab) thus increases bone formation, bone mass and bone strength in models of osteopenia and fracture repair. This study assessed the therapeutic potential of Scl-Ab to stimulate alveolar bone regeneration following experimental periodontitis (EP). Ligature-induced EP was induced in rats to generate localized alveolar bone defects. Following 4 weeks of disease induction, Scl-Ab (þEP) or vehicle (þ/À EP) were systemically delivered, twice weekly for up to 6 wks to determine the ability of Scl-Ab to regenerate bone around toothsupporting osseous defects. 3 and 6 wks after the initiation of Scl-Ab or vehicle treatment, femur and maxillary jawbones were harvested for histology, histomorphometry, and micro-computed tomography (micro-CT) of linear alveolar bone loss (ABL) and volumetric measures of bone support, including bone volume fraction (BVF) and tissue mineral density (TMD). Serum was analyzed to examine bone turnover markers during disease and regenerative therapy. Vehicle þ EP animals exhibited maxillary bone loss (BVF, TMD and ABL) at ligature removal and thereafter. 6 weeks of Scl-Ab significantly improved maxillary bone healing, as measured by BVF, TMD and ABL, when compared to vehicle þ EP. After 6 weeks of treatment, BVF and TMD values in the Scl-Ab þ EP group were similar to those of healthy controls. Serum analysis demonstrated higher levels of bone formation markers osteocalcin and PINP in Scl-Ab treatment groups. Scl-Ab restored alveolar bone mass following experimental periodontitis. These findings warrant further exploration of Scl-Ab therapy in this and other oral bone defect disease scenarios.

A Review of Osteocyte Function and the Emerging Importance of Sclerostin

“…Sclerostin antibody administered to rats with a critical-sized femoral defect and mice with a non-criticalsized femoral defect showed earlier healing, complete union, and physiologic maturation of the defect 71,72 . Similar conclusions can be drawn from the rat model of experimental periodontitis, in which sclerostin antibody treatment increased alveolar bone regeneration and filled substantial oral bone defects 73 .…”

Effect of sclerostin removal <i>in vivo</i> on experimental periodontitis in mice

“…Thus, we assume that anti-sclerostin antibody is able to stimulate bone regeneration after experimental periodontitis, and even for periodontitis which sometimes may be caused by orthodontic treatment or obesity. (28,29). In addition, a single-dose placebo-controlled randomized clinical trial of anti-sclerostin antibody has suggested that further clinical investigations of sclerostin inhibition as a potential therapeutic strategy would be justified for patients in whom increased bone formation is necessary (30).…”

Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation

“…It is secreted by osteocytes and acts on cells along the endosteal surfaces (58,59), and inhibits the binding of Wnts to LRP5 (3,60). The inhibitory effects of SOST on Wnt signaling and bone formation can be ameliorated by a monoclonal antibody, which has been shown to increase bone mass in postmenopausal women in clinical trials and improve fracture healing and osteogenesis imperfecta in animal models (14,16,17). Hence, it has garnered a lot of attention for its promise as a bone anabolic drug.…”

“…These findings further underscore the importance of studying the identity and role of Wnt-producing cells in bone development. Furthermore, the antibody blocking SOST is effective in ameliorating catabolic skeletal diseases, like osteogenesis imperfecta (14) and osteoporosis in rats (15), and improves fracture healing (16). Currently, the anti-SOST antibody is undergoing clinical trials in the treatment of osteoporosis and the preliminary results are promising (17).…”