Dentoalveolar Alterations in an Adenine‐Induced Chronic Kidney Disease Mouse Model

Abstract

Chronic kidney disease (CKD) is characterized by kidney damage and loss of renal function. CKD mineral and bone disorder (CKD–MBD) describes the dysregulation of mineral homeostasis, including hyperphosphatemia and elevated parathyroid hormone (PTH) secretion, skeletal abnormalities, and vascular calcification. CKD–MBD impacts the oral cavity, with effects including salivary gland dysfunction, enamel hypoplasia and damage, increased dentin formation, decreased pulp volume, pulp calcifications, and altered jaw bones, contributing to clinical manifestations of periodontal disease and tooth loss. Underlying mechanisms are not fully understood, and CKD mouse models commonly require invasive procedures with high rates of infection and mortality. We aimed to characterize the dentoalveolar effects of an adenine diet (AD)‐induced CKD (AD–CKD) mouse model. Eight‐week‐old C57BL/6J mice were provided either a normal phosphorus diet control (CTR) or adenine and high‐phosphorus diet CKD to induce kidney failure. Mice were euthanized at 15 weeks old, and mandibles were collected for micro–computed tomography and histology. CKD mice exhibited kidney failure, hyperphosphatemia, and hyperparathyroidism in association with porous cortical bone in femurs. CKD mice showed a 30% decrease in molar enamel volume compared to CTR mice. Enamel wear was associated with reduced ductal components, ectopic calcifications, and altered osteopontin (OPN) deposition in submandibular salivary glands of CKD mice. Molar cusps in CKD mice were flattened, exposing dentin. Molar dentin/cementum volume increased 7% in CKD mice and pulp volume decreased. Histology revealed excessive reactionary dentin and altered pulp‐dentin extracellular matrix proteins, including increased OPN. Mandibular bone volume fraction decreased 12% and bone mineral density decreased 9% in CKD versus CTR mice. Alveolar bone in CKD mice exhibited increased tissue‐nonspecific alkaline phosphatase localization, OPN deposition, and greater osteoclast numbers. AD–CKD recapitulated key aspects reported in CKD patients and revealed new insights into CKD‐associated oral defects. This model has potential for studying mechanisms of dentoalveolar defects or therapeutic interventions. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Cdc42 deletion yielded enamel defects by disrupting mitochondria and producing reactive oxygen species in dental epithelium

“… 39 Tooth development under hypoxia enhances the clinical prevalence of DDE. 40 Less enamel matrix and lower calcified enamel demonstrated impaired ameloblast differentiation upon epithelium-specific Cdc42 deletion. Ameloblast differentiation requires energy, and mitochondria are involved in Ca 2+ signaling.…”

Pathogenesis and Mechanism of Uremic Vascular Calcification

“…Moreover, mice are small animals with a limited blood volume and a high mortality rate [ 14 ]. An adenine diet (0.2% adenine + 1.8% phosphorus) has been demonstrated to induce rapid and remarkable changes in the alveolar bone of CKD mice, including enamel loss, increased dentin, decreased pulp, and severe alveolar bone resorption [ 18 ]. A study by Zhang et al compared the effect of an eight-week low-calcium and high-phosphorus diet (0.6% calcium and 1.2% phosphorus) in the 5/6 nephrectomy model, adriamycin model, and ureter ligation model.…”

Development, Establishment, and Validation of a Model for the Mineralization of Periodontium Remodelling Cells: Cementoblasts

“…In addition, periodontitis is a well-known comorbidity of prevalent chronic diseases such as chronic kidney disease [ 4 ]. Recently, in vivo methods are being developed to study alveolar defects resulting from diseases such as CKD [ 5 ], highlighting the need to study the clinical implications of dental dysfunction resulting from other systemic diseases. However, in vitro methods to study the mechanisms involved have not been established yet.…”