Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats.

Sclerostin antibodies increase bone mass by stimulating bone formation. However, human and animal studies show that bone formation increases transiently and returns to pre-treatment level despite ongoing antibody treatment. To understand its mechanism of action, we studied the time course of bone formation, correlating the rate and extent of accrual of bone mass and strength after sclerostin antibody treatment.

Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined.

Efficacy of a sclerostin antibody compared to a low dose of PTH on metaphyseal bone healing.

We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 weeks the animals then received injections of either phosphate buffered saline (control), sclerostin antibody (25 mg/kg, twice weekly) or PTH (5 µg/kg, daily).

In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma.

Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated.

Dose-dependent enhancement of spinal fusion in rats with teriparatide (PTH[1-34]).

Study Design: Controlled animal experiments.

Objective: To test the dose and efficacy of teriparatide in a rat spinal fusion model.

Summary Of Background Data: Teriparatide was shown to enhance spinal fusion in rats and rabbits previously, but the dose-dependent effect of teriparatide in spinal fusion in rats was not well characterized.

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions.

The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma.

p21CIP-1/WAF-1 induction is required to inhibit prostate cancer growth elicited by deficient expression of the Wnt inhibitor Dickkopf-1.

Osteoblastic bone metastases are the most common metastases produced by human prostate cancers (PCa). Deregulated activity of Wnt growth factors resulting from overexpression of the Wnt inhibitor Dickkopf-1 (DKK-1) is known to contribute to formation of the osteoblastic component of PCa skeletal bone metastases. In this study, we report that DKK-1 knockdown in osteolytic human PCa cells unexpectedly delays the development of both soft tissue and osseous lesions.

Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation.

Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity.

IL-1beta epitope mapping using site-directed mutagenesis and hydrogen-deuterium exchange mass spectrometry analysis.

Hu007, a humanized IgG1 monoclonal antibody, binds and neutralizes human, cynomolgus, and rabbit IL-1beta but only weakly binds to mouse and rat IL-1beta. Biacore experiments demonstrated that Hu007 and the type-I IL-1 receptor competed for binding to IL-1beta. Increasing salt concentrations decrease the association rate with only moderate effects on the dissociation rate, suggesting that long-range electrostatics are critical for formation of the initial complex.