1942 Fig. 2 Multiple factors may contribute to decreased bone formation in chronic kidney disease Pediatr Nephrol (2011) 26:1937–1946 Vitamin D deficiency Uremic toxins Hyperparathyrodism Metabolic acidosis Uremic cachexia Pro-inflammatory cytokines (IL-1α , IL-6, TNF-α , TGF-β , leptin) Y receptor & NPY deranged bone turnover of uremic patients [96]. Osteoblastic IL-6 secretion was negatively associated with osteoblastic cell growth in dialysis patients with low bone turnover [97]. Increased expression of IL-1α, IL-6, TNF-α, and TGF-β has been demonstrated in bone marrow in ESRD patients. IL-6 and TGF-β were also detected in osteoblasts and osteocytes. The extent of cytokine deposition corresponded to the severity of renal osteodystrophy [98], suggesting an impor- tant role of cytokines in the pathogenesis of renal osteodys- trophy. IL-6 exerts its action by binding to its receptor (IL6R) and transduces subsequent signaling within cells. In vitro as well as in vivo data point to IL-6 as an autocrine/ paracrine factor in bone osteoclasts. Increased mRNA expression of IL-6 and IL6R was found in osteoclasts and bone marrow cells in iliac crest bone biopsies from ESRD patients [99]. Thus, chronic inflammation in CKD has a negative impact on bone remodeling. Pro-inflammatory cytokines may contribute to the pathogenesis of renal osteodystrophy. Neuropeptides and bone mass regulation in chronic kidney disease Cytokines signal through CNS and influence bone remodeling [100, 101]. Central to this hypothesis is the discovery that leptin is an important regulator of bone mass. The characterization of the sympathetic nervous system as a regulator of bone remodeling has led to several clinical studies demonstrating a substantial protec- tive effect of ß-blockers, particularly ß1-blockers, on fracture risk [102]. Studies in several model organisms have reinforced the role of the CNS in the regulation of bone remodeling by the identification of several additional genes such as melanocortin 4 receptor (MC4R), neuro- peptide Y (NPY), Y2 receptor, cannabinoid receptor CB1 (Cnbr1), and the genes of the circadian clock [101]. These genes have several common features, including high levels of expression in the hypothalamus and the ability to regulate other major physiological functions in addition to Osteoblast activity Osteoclast activity Bone mass in CKD bone remodeling including energy homeostasis, body weight, and reproduction. Leptin plays a key role in skeletal physiology. Leptin- deficient (ob/ob), leptin receptor-deficient (db/db) and lip- odystrophic mice, all of which exhibit decreased leptin signaling, have the same high bone mass phenotype [103]. Leptin is cleared from the circulation by the kidney [104, 105]. In CKD patients, serum levels of leptin were significantly increased [105, 106]. Elevated leptin level is a potent inhibitor of bone formation [100, 103]. High serum leptin levels are reported in several disorders, typically associated with osteopenia, such as liver cirrhosis, type 2 diabetes, and ESRD [107]. An inverse correlation between serum leptin levels and histomorphometric indicators of bone turnover has been demonstrated in renal bone disease. Serum leptin inversely correlated with PTH, bone formation rate, and mineral deposition rate in chronic dialysis patients. A complementary analysis in the same study in male dialysis patients revealed that the risk for low turnover bone disease increases with serum leptin concentrations. Adynamic bone disease is five times higher in patients with high serum leptin (third tertile) than those with relatively low serum leptin (first tertile) [108]. We demonstrated that elevated leptin levels may be an important cause of uremia-associated cachexia via signaling through the hypothalamic melanocortin system [109]. Leptin signaling is an important regulator of bone metabolism. Leptin acts centrally through the hypothalamic melanocortin receptors to affect appetite, metabolic rate, and bone mass [100]. Patients with loss-of-function mutations of melanocortin-4 receptor (MC4R) have markedly increased total body BMC and increased BMD [110], suggesting that leptin may regulate bone mass by increasing melanocortin receptor mediated signaling. We evaluated the role of leptin and melanocortin signaling on bone mass and bone strength in a mouse model of uremia. We showed that uremia induced in c57Bl/6J mice by subtotal nephrectomy resulted in elevated BUN, creatinine, and circulating leptin levels compared to pair-fed sham-operated mice. Whole-body and femoral BMC/BMD in nephrectomized c57Bl/6J mice were