Farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate pathway, is the inhibition target of alendronate, a potent FDA-approved nitrogen-containing bisphosphonate (N-BP) drug, at the molecular level. Alendronate not only inhibits osteoclasts, but also has been reported to positively affect osteoblasts. This study assesses the knock-down effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures. Primary murine bone marrow cell-induced osteoclasts and the preosteoblast MC3T3-E1 cell line were used to assess effects of anti-FPPS siRNA compared with alendronate. Results show that both FPPS mRNA message and protein knock-down in serum-based culture is correlated with reduced osteoclast viability. FPPS siRNA is more potent than 10μM alendronate, but less potent than 50μM alendronate on reducing osteoclast viability. Despite FPPS knock-down, no significant changes were observed in osteoblast proliferation. FPPS knock-down promotes osteoblast differentiation significantly but not cell mineral deposition. However, compared with 50μM alendronate dosing, FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation. Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization. Overall, results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast-mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways.

The pharmacological action of peroxisome proliferator-activated receptor (PPAR)γ in promoting sodium and water retention is well documented as highlighted by the major side-effect of body weight gain and edema associated with thiazolidinedione use. However, a possible physiological role of PPARγ in regulation of fluid metabolism has not been reported by previous studies. Here we analyzed fluid metabolism in inducible whole-body PPARγ knockout mice. The null mice developed severe polydipsia and polyuria, reduced urine osmolality, and modest hyperphagia. The phenomenon persisted during 3 days of pair feeding and pair drinking, accompanied by progressive weight loss. After 24 h water deprivation, the null mice had a lower urine osmolality, a higher urine volume, a greater weight loss, and a greater rise in hematocrit than the floxed control. Urinary vasopressin (AVP) excretion was not different between the genotypes under basal condition or after WD. The response of urine osmolality to acute and chronic 1-desamino-8-D-arginine vasopressin treatment was attenuated in the null mice, but the total abundance or phosphorylation of aquaporin 2 (AQP2) in the kidney or AVP-induced cAMP production in inner medullary collecting duct suspensions was unaffected. Overall, PPARγ participates in physiological control of fluid homeostasis through an unknown mechanism involving cAMP/AQP2-independent enhancement of AVP response.

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