Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model?

Abstract

Background Sclerostin is a secreted glycoprotein that inhibits the intracellular Wnt signaling pathway, which, when inactivated, stimulates bone formation. This has been seen in fracture studies, which have shown larger and stronger calluses with accelerated fracture healing in sclerostin knockout and sclerostin antibody injection models. However, the effects of these two mechanisms have not been compared in the context of fracture healing. Questions/purposes We sought to determine the degree to which sclerostin inhibition (Scl-Ab injection) and complete sclerostin depletion inhibit fracture healing in a mouse model as evaluated by (1) morphometric trabecular bone measures at the fracture site, and (2) fracture site structural strength. Methods Ten-week-old male sclerostin knockout (n = 20) and wild type (n = 40) mice underwent insertion of a tibial intramedullary pin after which a midshaft tibial osteotomy was performed. The mice were divided in three groups: sclerostin knockout (n = 20), wild type with sclerostin antibody injection (intravenous dose of 100 mg/kg weekly) (n = 20), and wild type with saline injection (n = 20). The mice for each group where subdivided and euthanized at 14, 21, 28, and 35 days after surgery, at which time the fractured tibias were assessed with microCT (to assess morphometric trabecular bone measures: bone volume to total volume (BV/TV), trabecular thickness, trabecular number, and structural model index at the fracture site. Biomechanical testing in the form of three-point bending also was done to assess fracture site structural strength. A difference greater than 3.7% in our primary outcome (BV/

Notch Signaling Participates in TGF‐β‐Induced SOST Expression Under Intermittent Compressive Stress

“…Sclerostin, a protein encoded by the SOST gene, is a Wnt signaling antagonist and is a negative regulator of bone formation (Semenov et al, ). Mice injected with a sclerostin neutralizing antibody and sclerostin knockout mice exhibited increased trabecular bone at fracture sites, demonstrating that sclerostin depletion enhances bone fracture healing in mice (Alzahrani et al, ). Similarly, deleting the Sost gene rescues periodontal defects in a periostin‐null periodontitis mouse model (Ren et al, ).…”

Augmentation of fracture healing by hydroxyapatite/collagen paste and bone morphogenetic protein‐2 evaluated using a rat femur osteotomy model

“…A clinical trial using this antibody to treat osteoporosis is currently in progress . Systemic administration of both drugs has been reported as effective for augmenting fracture healing in animals . Furthermore, teriparatide has been clinically proven to augment fracture healing under certain sets of conditions …”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…Sost antibody treatment on T2DM rats with a low bone mass phenotype has also revealed increased bone formation, however this effect has not been examined in T1DM mice [94]. Sost antibody have also shown an anabolic effect in fracture healing with enhanced bone formation and is mechanically stable [95]. Due to the positive effects of Sost antibody treatment on fracture healing [96], this may be the ideal treatment for impaired fracture in diabetic patients, as well as possibly serving a protective role against fracture risk for T1DM patients with osteoporosis.…”