Increased Osteoblastic Activity and Expression of Receptor Activator of NF-κB Ligand in Nonuremic Nephrotic Syndrome

Abstract

Patients with nephrotic syndrome (NS), even with normal GFR, often display altered mineral homeostasis and abnormal bone histology. However, the latter, mostly osteomalacia and increased bone resorption, cannot be readily explained by the prevalent concentrations of parathyroid hormone and vitamin D metabolites. The transmembrane receptor activator of NF-B ligand (RANKL) of osteoblasts is essential for osteoclast formation and differentiation. Osteoblasts activity and the expression of RANKL were tested in cultures of normal human osteoblasts with sera obtained from patients with NS and normal GFR (129 ؎ 26 ml/min per 1.73 m 2 ) during relapse and remission of their NS. Osteoblasts that were cultured in vitro with sera during relapse displayed elevated concentrations of alkaline phosphatase (AP) and increased expression of RANKL. By contrast, during remission, AP concentrations were significantly lower (P < 0.05) and RANKL expression notably attenuated or absent. AP correlated with the proteinuria (r ‫؍‬ 0.5, P < 0.05) and was not significantly affected by the therapeutic administration of corticosteroids. Whereas parathyroid hormone levels were normal (35 ؎ 21 pg/ml), the serum markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) were lower during relapse compared with remission. Thus, sera from patients with NS and normal GFR stimulate the activity of osteoblasts and upregulate their expression of RANKL. These alterations, more prominent during clinically active NS, are transient and reversible upon remission. These disturbances of bone biology may play an important pathogenic role in the abnormal bone histology observed in patients with NS even before a decline in GFR occurs.

Bone mineral content and mineral metabolism during cyclosporine treatment of nephrotic syndrome

“…In fact, up-regulation of the osteoclastactivator receptor activator of nuclear factor k-B ligand (RANKL), an important mechanism of bone loss independent of Cy, was recently demonstrated in normal human osteoblasts exposed to sera from children with active NS. 57 The findings in the present study of normal BMD in most patients during Cy-Rx and while in clinical remission, challenge the notion of a primary role of Cy in the bone loss of Tx patients 49 and point to the importance of other preexisting or concurrent factors independent of Cy as causes for the bone loss. 1,48,57 …”

“…57 The findings in the present study of normal BMD in most patients during Cy-Rx and while in clinical remission, challenge the notion of a primary role of Cy in the bone loss of Tx patients 49 and point to the importance of other preexisting or concurrent factors independent of Cy as causes for the bone loss. 1,48,57 …”

RANKL Is a Mediator of Bone Resorption in Idiopathic Hypercalciuria

“…This result was unexpected because OPG inhibits osteoclastogenesis. The association of RANKL with elevated bone resorption has already been suggested in other studies that involved molecular biology techniques and focused on other renal or nonrenal diseases (37)(38)(39)(40); however, reports of serum concentration of OPG have shown OPG to be significantly higher rather than lower in women with postmenopausal osteoporosis than in age-matched control subjects (41,42), what the authors attributed to a compensatory response to the enhanced bone resorption. Because immunohistochemical studies in human bone tissue quantifying RANKL or OPG are scant, the hypothesis of a higher bone expression of OPG counteracting RANKL at a bone level presently observed may be raised on basis of the results of serum levels of cytokines (41).…”

Serum RANKL, osteoprotegerin (OPG), and RANKL/OPG ratio in nephrotic children

“…Freundlich et al [21] observed an up-regulation of RANKL in normal osteoblasts incubated with sera of NS children in relapse and normal expression in those incubated with sera of NS children in remission; this result suggests that changes in RANKL expression in NS children are transient and reversible. The study of Faienza et al [22] showed a down-regulation of OPG and over-expression of RANKL in T-cells from patients with a 21-hydroxylase deficiency who were treated with GCS, compared with controls.…”