#1865 The role of osteoclast-associated receptor in phosphorus metabolism via salivary-bone-kidney interaction
Nephrology Dialysis Transplantation(2024)
摘要
Abstract Background and Aims We have identified osteoclast-associated receptor (OSCAR) in the osteoclasts and salivary proline-rich proteins (S-PRPs), which are specifically secreted from the salivary glands and are carrier proteins for calcium and phosphorus, as new factors involved in phosphorus metabolism using bulk RNA sequencing of all organs in a high-phosphate (HP) loaded mouse model with kidney disease. The roles of OSCAR have been reported to include activation of NFATc1, which is essential for osteoclast differentiation, and inhibition of apoptosis. However, to our knowledge, no study has examined the relationship between OSCAR and chronic kidney disease-mineral bone disorder (CKD-MBD). In this study, we investigated the role of OSCAR in phosphorus metabolism particularly involving the salivary grands (S-PRPs) in mice models of high phosphorus load and kidney disease. Method We used 11- to 13-week C57BL/6N male mice to compare phosphorus metabolism between wild-type (WT) and OSCAR knockout (KO) mice. WT and OSCAR KO mice underwent sham surgery (Ctrl group) or 5/6 nephrectomy (CKD group), followed by HP loading (1.8% phosphate diet) for 1 week. After HP loading, these mice were kept in metabolic gauges for 24 hours, during which urine and fecal samples were collected. Subsequently, blood and organ (parotid grand and kidney) samples were collected. The parotid grands, the main source of S-PRPs, were harvested after 1 week of HP loading, and specific mRNA for S-PRPs (Prb1 and Prpmp5) and for phosphate (Pi) transporter (NaPi2b and Pit-2), responsible for Pi reabsorption in primary saliva, were examined. Results In the non-CKD group, there were no significant difference in Pi homeostasis including plasma Pi, FGF23, PTH, or urinary, fecal, and salivary Pi excretion levels after HP loading. In the CKD group, OSCAR KO mice showed significantly lower urinary Pi excretion than WT mice (WT vs OSCAR KO; 25.43 ± 3.88 mg/day vs 17.65 ± 5.75 mg/day, P = .006) after HP loading, but no difference in fecal Pi excretion was seen between genotypes. HP-induced plasma intact and C-terminal FGF-23 elevations were significantly suppressed in OSCAR KO mice (WT vs OSCAR KO; 6857 ± 4484 pg/mL vs 1573 ± 524 pg/mL, P = .002), indicating that the increased FGF23 “production” was suppressed in HP-loaded CKD/OSCAR KO mice. In contrast, there was no difference in plasma PTH levels between OSCAR KO and WT mice (WT vs OSCAR KO; 4189 ± 1361 pg/mL vs 5082 ± 1120 pg/mL, P = .22). As a result, plasma Pi levels in WT mice were not significantly different from those in OSCAR KO mice after 1-week HP loading (WT vs OSCAR KO; 26.91 ± 7.76 mg/dL vs 28.87 ± 7.49 mg/dL, P = 0.61), suggesting an increased internal Pi burden to organs other than the blood stream such as bones and ectopic calcifications in OSCAR KO mice compared to WT mice after HP loading and CKD. In the parotid gland, S-PRPs encoding mRNA (Prb1 and Prpmp5) expressions were decreased in OSCAR KO mice compared to those in WT mice, with or without CKD. Pi reabsorption transporter mRNA expression in the parotid gland was also decreased in OSCAR KO mice compared to those in WT mice, with or without CKD, after 1-week HP loading, suggesting an increase in salivary Pi concentrations in OSCAR KO mice compared to WT mice. Conclusion These results suggest that OSCAR may regulate urinary Pi excretion via FGF-23 in the bone. OSCAR was also significantly associated with salivary Pi levels via S-PRPs and Pi transporter in the parotid grands. OSCAR regulate Pi homeostasis through interactions with the kidney, salivary grands, bone, and intestine.
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