Sclerostin, a product of osteocytes, is known to inhibit Wnt signaling by binding the LRP5/6 receptor.
We investigated the effects of a mutated mouse sclerostin protein (muScl, R118A/R144A) with potential sclerostin antagonistic activity. In vitro, muScl fully competed with wild type sclerostin for binding to LRP6, whereas its IC50 for Wnt3a activity was 4× higher than sclerostin (i.e. 600 nM). Moreover, serum osteocalcin increased in mice after short-term administration of muScl at 0.1 mg/kg, but not at 1 mg/kg.
Experiment 1: 3 month-old mice received muScl by minipumps (0.01 mg/kg per day and 0.05 mg/kg per day) or vehicle for 2 weeks. The left tibia was simultaneously subjected to axial compression (12 N, at 0.1 Hz, during 7 min, 3 days/week), whereas the right tibia served as non-loaded control. Compared to vehicle, muScl increased total body BMD at both doses (1.23 mg/cm2 vs −0.10 mg/cm2; P<0.05; 1.27 mg/cm2 vs −0.10 mg/cm2; P<0.05, respectively). However, neither dose affected bone microarchitecture in vertebrae, non-loaded or loaded tibia. In the non-stimulated lower limb, muscle mass weight tended to increase with muScl (P=0.09 vs vehicle).
Experiment 2: 2 month-old mice received muScl s.c. (0.05 mg/kg per day) or vehicle for 3 weeks, with/without axial compression for 2 weeks. MuScl did not significantly increase bone mass, however it increased the appendicular lean mass in the non-stimulated lower limb (113 vs 96%). Tibia trabecular BV/TV and cortical BV were lower in the muScl vs vehicle group (8 vs 13.3%; 0.41 vs 0.46 mm3; respectively, both P<0.05). No additive or synergistic effect was observed between mechanical stimulation and muScl.
In conclusion, at the dose of 0.01 mg/kg, muScl improved bone mass without microarchitecture changes, whereas at a higher dose it seemed to display inhibitory (sclerostin-like) activity on bone. Interestingly, muScl improved the appendicular lean and muscle mass, which would suggest a role of sclerostin in bonemuscle interactions.
18 - 21 May 2013
European Calcified Tissue Society