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Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is a newly defined syndrome encompassing patients with chronic kidney disease that have a triad of biochemical alterations in calcium, phosphorus and parathyroid hormone, vascular calcification, and bone abnormalities. Here we describe a novel Cy/+ rat model of slowly progressive kidney disease spontaneously developing the three components of CKD-MBD when fed a normal phosphorus diet. Since the renal disorder progressed 'naturally' we studied the effect of dietary manipulation during the course of the disease. Animals with early, but established, chronic kidney disease were fed a casein-based or a grain-based protein diet both of which had equivalent total phosphorus contents. The two different sources of dietary protein had profound effects on the progression of CKD-MBD, likely due to differences in intestinal bioavailability of phosphorus. Although both dietary treatments resulted in the same serum phosphorous levels, the casein-fed animals had increased urinary phosphorus excretion and elevated serum FGF23 compared to the grain-fed rats. This model should help identify early changes in the course of chronic kidney disease that may lead to CKD-MBD.

The primary macrophage growth factor, colony-stimulating factor-1 (CSF-1), is homodimeric and exists in 3 biologically active isoforms: a membrane-spanning, cell-surface glycoprotein (csCSF-1) and secreted glycoprotein (sgCSF-1) and proteoglycan (spCSF-1) isoforms. To investigate the in vivo role of the chondroitin sulfate glycosaminoglycan (GAG) chain of spCSF-1, we created mice that exclusively express, in a normal tissue-specific and developmental manner, either the secreted precursor of spCSF-1 or the corresponding precursor in which the GAG addition site was mutated. The reproductive, hematopoietic tooth eruption and tissue macrophage defects of CSF-1-deficient, osteopetrotic Csf1(op)/Csf1(op) mice were corrected by transgenic expression of the precursors of either sgCSF-1 or spCSF-1. Furthermore, in contrast to the transgene encoding csCSF-1, both failed to completely correct growth retardation, suggesting a role for csCSF-1 in the regulation of body weight. However, spCSF-1, in contrast to sgCSF-1, completely resolved the osteopetrotic phenotype. Furthermore, in transgenic lines expressing different concentrations of sgCSF-1 or spCSF-1, spCSF-1 more efficiently corrected Csf1(op)/Csf1(op) defects of tooth eruption, eyelid opening, macrophage morphology, and B-cell deficiency than sgCSF-1. These results indicate an important role of the CSF-1 chondroitin sulfate proteoglycan in in vivo signaling by secreted CSF-1.

The philosopher William of Ockham is recognized for the maxim that an assumption introduced to explain a phenomenon must not be multiplied beyond necessity, or that the simplest explanation is probably the correct explanation. The general truth is that conjugated linoleic acids (CLAs) are nutrients. However, the demonstration that these isomers of octadecadienoic acid protect against cancers in rodents stimulated curiosity that directed significant resources to characterize the biological functions of these fatty acids in cell and animal models. The benefits to human subjects given supplements of CLA were at best modest. The disappointing results in humans should be taken as an opportunity to critically evaluate all findings of CLA use and to consolidate the common actions of this nutrient so that future investigations focus on specific isomers and the most reasonable mechanisms. As such, the principal and consistently reported benefits of CLA have been in improving cancer outcomes, reducing body fat in growing animals, and modulating cell functions. Recognizing where related actions of CLA converge in specific disease conditions and physiologic states is how research efforts should be directed to minimize the pursuit of superfluous theories. Here, we briefly review the current biological effects of CLA and attempt to integrate their potential effect on the physiology and health of the skeletal system. Thus, the purpose of this review is to advance the science of CLA and to identify areas of research in which these nutrients affect bone metabolism and skeletal health.

The effects of dietary polyunsaturated fatty acids (PUFA) on ex vivo bone prostaglandin E(2) (PGE(2)) production and bone formation rate were evaluated in rats. Weanling male Sprague-Dawley rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 d. The dietary lipid treatments were formulated with safflower oil and menhaden oil to provide the following ratios of (n-6)/(n-3) fatty acids: 23.8 (SMI), 9.8 (SMII), 2.6 (SMIII), and 1.2 (SMIV). Ex vivo PGE(2) production in liver homogenates and bone organ cultures (right femur and tibia) were significantly lower in rats fed diets with a lower dietary ratio of (n-6)/(n-3) fatty acids than in those fed diets with a higher dietary ratio. Regression analysis revealed a significant positive correlation between bone PGE(2) and the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA), but significant negative correlations between bone formation rate and either the ratio of AA/EPA or PGE(2) in bone. Activities of serum alkaline phosphatase isoenzymes, including the bone-specific isoenzyme (BALP), were greater in rats fed a diet high in (n-3) or a low ratio of (n-6)/(n-3), further supporting the positive action of (n-3) fatty acids on bone formation. These results demonstrated that the dietary ratio of (n-6)/(n-3) modulates bone PGE(2) production and the activity of serum BALP in growing rats.

This study examined the effects of dietary fat on the fatty acid composition of liver and bone, and on the concentration of insulin-like growth factor-I (IGF-I) in liver and bone, as well as the relationship of these factors to bone metabolism. Day-old male broiler chicks were given a semipurified diet containing one of four lipid sources: soybean oil (SBO), butter+corn oil (BC), margarine+corn oil (MAC), or menhaden oil+corn oil (MEC) at 70 g/kg of the diet. At 21 and 42 d of age, chicks fed MEC had the highest concentration of (n-3) fatty acids [20:5(n-3), 22:5(n-3) and 22:6(n-3)] in polar and neutral lipids of cortical bone but the lowest amount of 20:4(n-6) in polar lipids. Diets containing t-18:1 fatty acids (MAC and BC) resulted in t18:1 accumulation in bone and liver. Bone IGF-I concentration increased from 21 to 42 d in chicks given the SBO and BC diets. Tibial periosteal bone formation rate (BFR) was higher in chicks given BC compared with those consuming SBO and MEC at 21 d. The higher BFR and concentrations of hexosamine in serum and IGF-I in cartilage, but lower 20:4(n-6) content in bone polar lipids in chicks given BC compared with those given SBO suggest that BC optimized bone formation by altering the production of bone growth factors. A second study confirmed that dietary butter fat lowered ex vivo prostaglandin E2 production and increased trabecular BFR in chick tibia. These studies showed that dietary fat altered BFR perhaps by controlling the production of local regulatory factors in bone.

Prenatal exposure to cocaine has been shown to produce a variety of effects on skeletal development and mineralization in humans, mice, and rats. The effects of cocaine on bone cell function and mineral metabolism pre- and postnatally are poorly understood. The present study examined the long term effects of prenatal cocaine exposure on femoral growth and mineralization in male rats. Pregnant rats were given 80 or 100 mg cocaine hydrochloride/kg during days 7-20 of gestation. At birth, body weights of pups born to these females were significantly decreased compared to normal and pair-fed controls. At the termination of the study (32 weeks), body weights of offspring from C100-treated females were still lower than normal. Long term effects of prenatal exposure to cocaine on femoral growth were most pronounced in offspring of C80-treated females. Femur dry weight, ash weight, organic matrix weight and density were significantly reduced in these animals compared to normal or pair-fed controls. The apparent osteopenic effects of prenatal exposure to cocaine suggests some long term postnatal impact on bone cell or mineral metabolism. Previous studies of cocaine use during pregnancy in humans and animals have focused primarily on physical and behavioral defects in offspring. The present findings indicate that prenatal exposure to cocaine may also have long term consequences to the skeleton.