Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3

Abstract Context: Osteocytes express proteins that regulate bone remodeling and mineralization. Objective: To evaluate the relationship between osteocyte-specific protein expression and bone histology in patients with monogenic osteoporosis due to wingless integration site 1 (WNT1) or plastin 3 (PLS3) mutations. Design and Setting: Cross-sectional cohort study at a university hospital. Participants: Six patients (four males; ages: 14 to 72 years) with a heterozygous WNT1 mutation and five patients (four males; ages: 9 to 70 years) with a heterozygous/hemizygous PLS3 mutation. Methods and Main Outcome Measures: Immunohistochemistry was performed for fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), sclerostin, and phosphorylated (phospho–)β-catenin in iliac crest samples and compared with bone histomorphometry. Results: FGF23 expression in WNT1 patients was 243% that observed in PLS3 patients (P < 0.01). DMP1, sclerostin, and phospho–β-catenin expression did not differ between groups. Serum phosphate correlated inversely with FGF23 expression (r = −0.79, P = 0.01) and serum ionized calcium correlated inversely with sclerostin expression (r = −0.60, P = 0.05). Phospho–β-catenin expression correlated inversely with DMP1 expression (r = −0.88, P < 0.001), osteoid volume/bone volume (r = −0.68, P = 0.02), and bone formation rate (r = −0.78, P < 0.01). FGF23 expression did not correlate with DMP1 expression, sclerostin expression, or bone histomorphometry. Marrow adiposity was higher in WNT1 than in PLS3 patients (P = 0.04). Conclusions: Mutations that disrupt WNT signaling and osteocytic mechanosensing affect osteocyte protein expression. Abnormal osteocyte function may play a role in the pathogenesis of monogenetic forms of osteoporosis. We studied bone from six WNT1 and five PLS patients. Bone FGF23 was higher in WNT1 than in PLS3 patients. Phospho–β-catenin correlated inversely with DMP1 and with bone turnover.