Abstract:
BACKGROUND : Sclerosteosis, a severe autosomal recessive sclerosing skeletal dysplasia characterised by excessive
bone formation, is caused by absence of sclerostin, a negative regulator of bone formation that binds LRP5/6 Wnt
co-receptors. Current treatment is limited to surgical management of symptoms arising from bone overgrowth.
This study investigated the effectiveness of sclerostin replacement therapy in a mouse model of sclerosteosis.
METHODS : Recombinant wild type mouse sclerostin (mScl) and novel mScl fusion proteins containing a C-terminal
human Fc (mScl hFc), or C-terminal human Fc with a poly-aspartate motif (mScl hFc PD), were produced and
purified using mammalian expression and standard chromatography methods. In vitro functionality and efficacy of
the recombinant proteins were evaluated using three independent biophysical techniques and an in vitro bone
nodule formation assay. Pharmacokinetic properties of the proteins were investigated in vivo following a single
administration to young female wild type (WT) or SOST knock out (SOST-/-) mice. In a six week proof-of-concept
in vivo study, young female WT or SOST-/- mice were treated with 10 mg/kg mScl hFc or mScl hFc PD (weekly), or
4.4 mg/kg mScl (daily). The effect of recombinant sclerostin on femoral cortical and trabecular bone parameters
were assessed by micro computed tomography (μCT).
RESULTS : Recombinant mScl proteins bound to the extracellular domain of the Wnt co-receptor LRP6 with high
affinity (nM range) and completely inhibited matrix mineralisation in vitro. Pharmacokinetic assessment following
a single dose administered to WT or SOST-/- mice indicated the presence of hFc increased protein half-life from
less than 5 min to at least 1.5 days. Treatment with mScl hFc PD over a six week period resulted in modest but
significant reductions in trabecular volumetric bone mineral density (vBMD) and bone volume fraction (BV/TV),
of 20% and 15%, respectively.
CONCLUSION : Administration of recombinant mScl hFc PD partially corrected the high bone mass phenotype in
SOST-/- mice, suggesting that bone-targeting of sclerostin engineered to improve half-life was able to negatively
regulate bone formation in the SOST-/- mouse model of sclerosteosis.
THE TRANSACTIONAL POTENTIAL OF THIS ARTICLE : These findings support the concept that exogenous sclerostin can reduce
bone mass, however the modest efficacy suggests that sclerostin replacement may not be an optimal strategy to
mitigate excessive bone formation in sclerosteosis, hence alternative approaches should be explored.
