CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Abstract

In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD-mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-a, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder. CKD is a pandemic affecting 26 million Americans in its early stages. 1 CKD is associated with high rates of cardiovascular mortality, making it much more likely that affected individuals will sustain cardiovascular morbidity, including death, than reach end stage kidney disease that requires RRT.

Skeletal inflammation and attenuation of Wnt signaling, Wnt ligand expression, and bone formation in atherosclerotic ApoE-null mice

“…In these mice, partial nephrectomy not only increases Ca, Pi, and PTH but also further reduces osteoblast number, bone formation rate, and bone mass (13,16). Interestingly, these changes are associated with a dramatic, but transient, increase in the level of circulating Dkk1, which is apparently produced by regenerating renal tissue.…”

“…This diet has been shown to cause renal damage in ApoE-KO mice, as evidenced by macrophage infiltration and increased inflammatory cytokine expression (50). In contrast, LDL receptor-null mice fed a cholate-free HFD do not exhibit renal damage or increased serum Ca and PTH; however, this HFD in combination with partial nephrectomy causes a rise in both (16). Thus, hypercalcemia and hyperparathyroidism occur in HFD-fed murine models of atherosclerosis regardless of whether reduced renal function results from surgical or chemical (cholate) intervention, albeit the hypercalcemia appears more extreme in the latter.…”

“…The deleterious effects of oxLDL on bone are not caused solely by kidney damage, since bone loss due to a decrease in osteoblast number also occurs in cholate-free HFD-fed LDL receptor-null mice with intact renal function (16). In these mice, partial nephrectomy not only increases Ca, Pi, and PTH but also further reduces osteoblast number, bone formation rate, and bone mass (13,16).…”

Metabolismo mineral óseo en pacientes con enfermedad renal crónica: revisión sobre su fisiopatología y morbimortalidad

“…Adicionalmente, inhibe la apoptosis de las células musculares lisas de los vasos sanguíneos (45) . En modelos animales de ERC los ratones CKD-2 mostraron incremento en la producción de inhibidores de Wnt (wingless/integration) como Dickkopf-1 (Dkk1) y esclerostina y disminución de Klotho soluble (46) . La vía Wnt canónica es una vía integrativa que tiene un rol importante en la formación ósea promoviendo la proliferación osteoblástica, la inducción de la osteoblastogénesis, la inhibición de la apoptosis osteocítica y osteoblástica y la atenuación de la osteoblastogénesis (46) .…”

“…En modelos animales de ERC los ratones CKD-2 mostraron incremento en la producción de inhibidores de Wnt (wingless/integration) como Dickkopf-1 (Dkk1) y esclerostina y disminución de Klotho soluble (46) . La vía Wnt canónica es una vía integrativa que tiene un rol importante en la formación ósea promoviendo la proliferación osteoblástica, la inducción de la osteoblastogénesis, la inhibición de la apoptosis osteocítica y osteoblástica y la atenuación de la osteoblastogénesis (46) . Al neutralizar Dkk1 en el modelo de CKD-2 en ratones, a través de la administración de anticuerpos monoclonales, luego de daño renal, se estimulaba la tasa de formación ósea, se corregía la osteodistrofia y se prevenía la calcificación vascular.…”