Background: Glucocorticoids (GCs) are frequently used to treat numerous chronic diseases in children. Beside their desired anti-inflammatory and immunosuppressive effects, GCs are well known to cause osteoporosis and impaired linear bone growth. These serious side effects of GCs have at least partially been linked to impairment of Wnt/β-catenin signalling. There is no therapy available to rescue from the undesired skeletal effects of GCs.
Objective and hypotheses: Our aim was to test whether lithium chloride (LiCl), an activator of non-canonical Wnt/β-catenin signalling, can rescue from GC-induced bone growth impairment.
Method: Foetal (days E1920) rat metatarsal bones (seven to nine bones per group) were dissected out and cultured with control medium (C), 1 μM dexamethasone (Dexa), 1 mM LiCl (L1), 10 mM LiCl (L10), or combination of drugs (Dexa+L1 and Dexa+L10) for 12 days. Pictures were taken at days 0 and 12 and the percent increase in bone length was calculated using Image J Software. Statistics was computed in R.
Results: Bone length increased by 141±12% when exposed to control medium. In contrast, Dexa-treated bones grew significantly less (115±12%; P=0.001 vs control). The growth of LiCl-treated bones was similar as in the control group (147±15 and 146±16% in the L1 and L10 groups respectively). When combining L10 and Dexa, bone growth was 147±20%, which was significantly better than in bones treated with Dexa only (115±12%; P=0.004). At a lower concentration (L1), LiCl did not rescue from Dexa-induced growth failure (121±19% vs 115±12% in Dexa only; P=0.44).
Conclusion: LiCl (10 mM) has the capacity to prevent GC-induced growth failure in cultured foetal rat metatarsal bones, an effect likely to be mediated through the non-canonical Wnt/β-catenin signalling pathway. As LiCl is already available for clinical use, our data could potentially open up for a new approach to prevent GC-induced growth failure in children.
Funding: This work was supported by ESPE Research Fellowship, sponsored by Novo Nordisk A/S.
01 Oct 2015 - 03 Oct 2015