Aims: The physiological function of sclerostin remains unknown. Sclerostin is synthesized by osteocytes and operates by inhibiting the Wnt/β-catenin pathway. Similarly, it is well established that low levels of sclerostin lead to enhanced bone formation and reduced calciuria, and that high levels of sclerostin are associated with osteoporosis.Methods: The impact of high levels of recombinant sclerostin on bone and mineral metabolism parameters was analyzed in this study. In male healthy rats, the effects of three elevated doses of sclerostin over a 14-day period were studied, involving bone histomorphometry, micro-CT (μCT), immunohistochemistry, and analysis of mineral metabolism parameters.Results: Although there was increased bone formation, high doses of sclerostin led to a higher reduction in trabecular bone volume due to a significant increase in bone resorption through the direct activation of osteoclastogenesis. In vitro, sclerostin promoted the differentiation of bone marrow stem cells into osteoclasts. Bone resorption, as measured by tartrate-resistant acid phosphatase (TRAP) activity, was excessive in trabecular, cortical, and subchondral bone. Similarly, high doses of sclerostin increased the number of hypertrophic chondrocytes, consequently expanding the growth plate area. At the cortical level, positive TRAP staining could be observed, suggestive of osteocytic osteolysis and trabecularization of cortical bone. The increased bone resorption resulted in a substantial rise in the urinary excretion of phosphorus and calcium, accompanied by elevated levels of FGF23 and a significant decrease in parathyroid hormone (PTH).Conclusion: These findings suggest that elevated levels of sclerostin promote bone resorption through the activation of osteoclasts and the generation of osteocytic osteolysis, resulting in increased calciuria, phosphaturia, and changes in mineral metabolism.Cite this article: Bone Joint Res 2025;14(5):448–462.

Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.

Chronic kidney disease (CKD) is associated with gut microbiota alterations that contribute to increased inflammation and the generation of uremic toxins and may worsen the disease progression. While probiotics may improve the pro-inflammatory cytokine profile, their effects on mineral metabolism, vascular calcification (VC), and CKD progression remain unclear. We aimed to evaluate the impact of a commercial probiotic (Probimel) supplementation on kidney function, mineral metabolism, inflammation and VC in both an experimental rat model and patients with advanced CKD and VC. The experimental model of VC was performed through 5/6 nephrectomy (Nx), a high-phosphate diet, and calcitriol. Animals were divided into three groups: Sham, Nephrectomy, and Nephrectomy + Probiotic. In the exploratory clinical study, 23 patients with advanced stage 5 CKD and VC were randomized and either received or did not receive daily probiotics for 6 months. Kidney function, mineral metabolism, uremic toxins, inflammation, VC, and fecal microbiota were evaluated. Probiotic supplementation decreased interleukin-6 (IL-6) and interpheron-γ (IFN-γ) and levels of the uremic toxin, indoxyl sulfate (IS), in the experimental model. However, no clear evidence of improvement in kidney function or vascular calcification was observed in either rats or patients with this probiotic. Under our experimental and clinical conditions, the selected probiotic did not modify key parameters related to CKD progression or VC.

The progression of chronic kidney disease (CKD) entails the development of complications, such as anemia and disturbances in mineral homeostasis, among others, and both of them have been shown to be closely related. In fact, high phosphorus (P) and excessive production of fibroblast growth factor 23 (FGF23) are hallmarks of the mineral alterations found in CKD, both of which have been associated with the development of anemia. The objective of this study was to evaluate whether the modulation of P load may impact the severity of CKD-related anemia as well as to separate the effects of FGF23 from those of P by the administration of an AntiFGF23 antibody while also investigating the involvement of hypoxia-inducible factor (HIF) signaling in these actions. To address this objective, we used a CKD model based on 5/6 nephrectomy (Nx). In a first experiment, CKD rats received diets with 0.2, 0.6, or 1.2% of P for 4 weeks. In a second study, Nx rats fed a 1.2% P diet were treated with an AntiFGF23 antibody for the same period. In an additional experiment, the effect of the exogenous administration of FGF23 and AntiFGF23 was evaluated. In all the experiments, we analyzed the hematological status, parameters of renal function and mineral metabolism, and HIF signaling. In CKD, the increase in P load was associated with an expected progressive elevation in FGF23 and an aggravation of anemia. In a situation of uremia with high P load, the neutralization of FGF23 restored hematological alterations while producing a significant inhibition in renal HIF1Alpha. In the absence of renal damage, the administration of recombinant FGF23 produced a decrease in serum iron and reticulocytes without changes in HIF signaling. In conclusion, progressive and concomitant increases in P and FGF23 produce an aggravation of anemia of renal origin. In this setting, the normalization of hematological parameters induced by FGF23 blockade is associated with the inhibition of renal HIF signaling. Thus, the implementation of FGF23-targeting therapies might constitute an additional strategy for the clinical management of CKD-related anemia.