Pediatr Nephrol (2011) 26:1937–1946 significantly lower than those in sham-operated mice. Femoral bone volume was markedly reduced in nephrec- tomized c57Bl/6J mice and this reduction was due to decreased cortical bone volume rather than cancellous bone volume. Cortical bone provides strength by being highly resistant to bending and torsion while cancellous bone has a vast surface area created by an interconnecting trabecular meshwork. The reduced femoral bone BMC/BMD and femoral cortical bone volume contributed to the observed reduction of femoral load to failure (a measure of bone strength and fracture risk) in nephrectomized c57Bl/6J mice. Agouti-related peptide (AgRP), a melanocortin receptor reverse agonist, was associated with increase in cortical bone volume but no change in cancellous bone volume as well as improved cortical bone strength [111]. These results in mice are consistent with clinical data from patients with CKD on dialysis in which decreases in cortical but not cancellous bone correlated with fracture risk. Hence, our results suggest that aberrant leptin signaling through mela- nocortin receptors may play an important role in the decreased bone mass and strength associated with CKD. Neuropeptide Y (NPY) is a target of leptin signaling in the hypothalamus and functions through its receptors. Immuno- reactivity of NPY is found in nerve fibers distributed throughout bone [112], strongly suggesting a role of NPY in the regulation of bone metabolism. NPY Y2-deficient mice display an increase in trabecular bone mass that can be reproduced by hypothalamus-specific deletion of Y2 gene [113], indicating that Y2 signaling in the hypothalamus inhibits bone formation. Recent studies indicate that signal- ing of Y2 receptor regulates, via a hypothalamic relay, the bone remodeling process in both femoral trabecular and cortical bone compartments [114]. Circulating levels of NPY are elevated in ESRD patients [115]. Whether the role of Y receptor and NPY signaling in bone metabolism is conserved from mouse to humans is unknown. Conclusions Chronic inflammatory diseases are characterized by systemic and local bone loss. The clinical picture is a composite of inflammatory lesions and structural damage, demonstrating the tight interaction between the immune and the skeletal system. Growing knowledge of the molecular mechanisms involved in the uncoupled bone metabolism has revealed potential targets for therapeutic interventions. Acknowledgements This work was supported by the Amgen Young Investigator Grant of the National Kidney Foundation to W.W.C. and grants from the National Institute of Health (K24 DK59574), Baxter Renal Discovery Program, and the Satellite Foundation to R.H.M. We thank Dr. Mary B. Leonard, University of Pennsylvania School of Medicine for valuable discussions and critical review of this manuscript. 1943 Disclosure of interests The authors have declared that no conflict of interest exists. RHM is supported by NIHU01 DK-03-012. WWC is supported by a young investigator award from the National Kidney Foundation. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References 1. Hardy R, Cooper MS (2009) Bone loss in inflammatory disorders. J Endocrinol 201:309–320 2. 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