Skeletal phenotypes in secreted frizzled-related protein 4 gene knockout mice mimic skeletal architectural abnormalities in subjects with Pyle’s disease from SFRP4 mutations

Abstract

Mutations in SFRP4 cause Pyle’s bone disease with wide metaphyses and increased skeletal fragility. The WNT signaling pathway plays important roles in determining skeletal architecture and SFRP4 is a secreted Frizzled decoy receptor that inhibits WNT signaling. Seven cohorts of male and female Sfrp4 gene knockout mice, examined through 2 years of age, had a normal lifespan but showed cortical and trabecular bone phenotypes. Mimicking human Erlenmeyer flask deformities, bone cross-sectional areas were elevated 2-fold in the distal femur and proximal tibia but only 30% in femur and tibia shafts. Reduced cortical bone thickness was observed in the vertebral body, midshaft femur and distal tibia. Elevated trabecular bone mass and numbers were observed in the vertebral body, distal femur metaphysis and proximal tibia metaphysis. Midshaft femurs retained extensive trabecular bone through 2 years of age. Vertebral bodies had increased compressive strength, but femur shafts had reduced bending strength. Trabecular, but not cortical, bone parameters in heterozygous Sfrp4 mice were modestly affected. Ovariectomy resulted in similar declines in both cortical and trabecular bone mass in wild-type and Sfrp4 KO mice. SFRP4 is critical for metaphyseal bone modeling involved in determining bone width. Sfrp4 KO mice show similar skeletal architecture and bone fragility deficits observed in patients with Pyle’s disease with SFRP4 mutations.

RUNX2‐related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4‐related Pyle disease

“…Loss of sFRP4's inhibitory function has shown to increase trabecular bone mass in Pyle disease cases by enhancing osteoblast activity and suppressing osteoclast formation. In contrast to a high bone mass phenotype in the trabecular bone compartment, sFRP4 deficiency leads to a reduction in cortical bone mass (cortical thinning) 8,17,18 . From a mechanistic point of view, it is interesting to note that homozygous LoF variants in SFRP4 can result in a similar skeletal phenotype as heterozygous GoF variants in RUNX2 .…”

“…In contrast to a high bone mass phenotype in the trabecular bone compartment, sFRP4 deficiency leads to a reduction in cortical bone mass (cortical thinning) 8,17,18. From a mechanistic point of view, it is interesting to note that homozygous LoF variants in SFRP4 can result in a similar skeletal phenotype as heterozygous GoF variants in RUNX2.…”

Sfrp4 is required to maintain Ctsk-lineage periosteal stem cell niche function

“…The association between mutations in SFRP4 and Pyle diseases has been sequentially confirmed ( 9 – 11 ). Sfrp4 deletion in mice causes limb and calvarial deformities closely mimicking those seen in individuals with Pyle disease ( 8 , 12 , 13 ). Using Sfrp4 −/− mice, we uncovered that in the long bones, Sfrp4 contributes to cortical bone homeostasis by regulating periosteal bone formation and endosteal remodeling ( 8 , 14 ).…”