DKK1 neutralizing antibody exhibits modest therapeutic effect in osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a group of monogenic skeletal diseases caused by defect of type I collagen. There is no specific treatment strategy and targeted therapy is urgently needed. Dickkopf-1 (DKK1), is a Wnt antagonist, and inhibition of DKK1 stimulates Wnt signaling and osteogenic capacity. Here, we used DKK1 neutralizing antibody (DKK1 nAb) to identify its effect on OI and clarify its effects on different types of OI. Mesenchymal stem cells (MSCs) derived from OI patients with variants in COL1A1 , COL1A2 , SERPINF1 , and WNT1 were treated with or without DKK1 nAb and induced toward osteoblast differentiation in vitro. In vivo, two Sprague-Dawley OI rat models carrying a Col1a2 (c.1000G > A) or Wnt1 (c.620G > A) mutation were administered DKK1 nAb for 2 and 4 weeks to assess skeletal therapeutic effects. In vitro, DKK1 nAb promoted osteogenic differentiation and mineralization and upregulated the mRNA levels of COL1A1 , COL1A2 , CTNNB1 , and RUNX2 in MSCs from some, though not all, OI patients. This regulatory effect is independent of the genotypes of OI patients. In vivo, a 2-week DKK1 nAb treatment exerted no significant improvement in skeletal parameters in either Col1a2 or Wnt1 mutant rats. While 4-week treatment showed modest improvement in trabecular bone in Col1a2 mutant OI rats, whereas no significant changes were detected in Wnt1 mutant OI rats. The DKK1 nAb demonstrates a modest therapeutic effect in OI, indicating its potential for some individuals, although the limited sample size necessitates caution in interpretation, and further validation in larger cohorts is warranted.