Impact of elevated sclerostin levels on bone resorption : unravelling structural changes and mineral metabolism disruption.

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. 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. 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). 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.