WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis

Abstract

Monogenic early-onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in WNT11 (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor LGR5, was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but WNT3A recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2–LGR5 complex via the non-canonical Wnt pathway.

wnt11f2 Zebrafish, an Animal Model for Development and New Insights in Bone Formation

“…Interestingly, we have recently shown that the heterozygous loss-of-function mutation of WNT11 in humans exhibits the opposite phenotype. 53 In a model of a WNT11 heterozygous mutant human osteoblast-like cell line generated by CRISPR-Cas9, we showed that the noncanonical pathway acts upstream of the canonical pathway, since in the absence of WNT11 , the canonical pathway could not be rescued 53 as was also observed in wnt11f2 tx226 mutant zebrafish. 5 This finding combined with our finding of HBM in wnt11f2 heterozygous zebrafish suggests that the noncanonical Wnt pathway is key to bone differentiation independent of bone patterning.…”

Wilforine inhibits rheumatoid arthritis pathology through the Wnt11/β-catenin signaling pathway axis

“…Wnt11 has an important promoting effect on cardiac tissue proliferation and tumor cell proliferation [ 15 – 19 ]. Given the similarity between synovial hyperplasia and angiogenesis in RA and cardiac tissue hyperplasia and tumor pathology, we investigated the expression changes and roles of Wnt11 in RA.…”

“…Wnt11 is one of the extracellular Wnt proteins involved in the Wnt signaling pathway. Wnt11 can activate the Wnt signaling by inducing the recombinant RSPO2/leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) complex through the noncanonical Wnt pathway [ 15 ]. Wnt11 also promotes angiogenesis by activating the atypical Wnt11/PKC/JNK signaling pathway [ 16 ].…”

Whole-Genome Scanning for Selection Signatures Reveals Candidate Genes Associated with Growth and Tail Length in Sheep

“…Interference with WNT11 led to inhibition of axial elongation of the embryo on the anterior and posterior axes [ 43 ]. WNT11 is also involved in the development of the skeletal system and contributes to bone homeostasis during osteogenic differentiation [ 44 ]. Alternatively, MSRB3 , HMGA2 , and PTCH1 have plausible biological functions associated with body size.…”