lp533401 and Disease-Models--Animal

Chronic kidney disease (CKD) is a pathological condition associated with renal osteodystrophy for which there are limited treatment options. Gut-derived serotonin (GDS) is one of the key signaling factors controlling the osteoblast proliferation. Previously, we shown that inhibition of GDS synthesis by LP533401 improved bone mineral status of rats with 5/6 nephrectomy-induced CKD model. Here, we investigated whether the use of LP533401 can modify GDS-dependent molecular pathway involved in osteoblast formation and bone mineralization in CKD rats. The 8-weeks of pharmacological manipulation after a complete CKD development reduced GDS and lead to the advantage of endogenous vitamin D [25(OH)D] over serotonin and parathyroid hormone (PTH) in rats treated with LP533401. The imbalance between GDS - 25(OH)D - PTH resulted in the intensified expression of cAMP- responsive element-binding protein (Creb), whereas the expression of myelocytomatosis oncogene (c-Myc) was simultaneously reduced. This lead to disruption of Foxo1- activating transcription factor 4 (Atf4) complex, and decrease in the expression of the major osteogenic markers. The weakening of excessive osteoblastogenesis was associated with better bone mineral status in all rats with CKD, and especially in LP533401-treated animals. In conclusion, the inhibition of GDS synthesis resulted in the mitigation of osteoblastogenesis observed in CKD, which translated into improvement of bone mineral status. This study provides key mechanistic insights into how modification of GDS-dependent molecular pathway affects bone mineral status in CKD and lays the groundwork for translating the role of functional serotonin signaling in the origin of impaired bone mineral status in patients with CKD.

Topics: Animals; Calcification, Physiologic; Disease Models, Animal; Male; Osteoblasts; Osteogenesis; Parathyroid Hormone; Pyrimidines; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Serotonin; Serotonin Agents

Klotho is a key regulator of phosphate and Ca. We evaluated the effect of LP533401 therapy on Klotho-expression-dependent Ca. Treatment with LP533401 and its vehicle resulted in the inhibition of transient receptor potential vanilloid receptor subtypes 5 and 6 (TRPV5, TRPV6) and calbindin (CaBP-28k, CaBP-9k) expression. The compensatory acceleration in renal expression of Na+/Ca. The modulation of circulating serotonin and its relation to other regulators of calcium handling can play an important role in calcium homeostasis and bone integrity in CKD rats treated with LP533401.

Topics: Animals; Bone and Bones; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Models, Animal; Glucuronidase; Klotho Proteins; Male; Pyrimidines; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Uremia; Vitamin D

LP533401 is an orally bioavailable small molecule that inhibits tryptophan hydroxylase-1, an enzyme responsible for the synthesis of gut-derived serotonin (GDS). Recently, we showed that increased GDS in rats with chronic kidney disease (CKD) affected bone strength and metabolism. We tested the hypothesis that treatment with LP533401 could reverse CKD-induced bone loss in uremia. Sixteen weeks after 5/6 nephrectomy, rats were randomized into untreated (CKD), treated with vehicle (VEH) and LP533401 at a dose of 30 or 100 mg/kg daily for 8 weeks. Treatment with LP533401 decreased serotonin turnover and restored bone mineral status, microarchitecture, and strength in CKD rats to the values observed in the controls. In parallel with the reduction of serotonin, serum phosphate levels also decreased, particularly in the LP533401, 100 mg/kg group. The mechanism underlying this phenomenon resulted from decreased expression of the renal VDR/FGF1R/Klotho/Npt2a/Npt2c axis, leading to elevated phosphate excretion in the kidneys. The elevated urinary phosphate excretion resulted in improved bone mineral status and strength in LP533401-treated rats. Unexpectedly, the standard VEH used in this model was able to reduce renal VDR/FGF1R/Klotho/Npt2a expression, leading to a compensatory increase in Npt2c mRNA levels, secondary disturbances in phosphate-regulated hormones and partial improvement in the mineral status of the trabecular bone. The decrease of serotonin synthesis together with the simultaneous reduction of renal Npt2a and Npt2c expression in rats treated with LP533401, 100 mg/kg led to an increase in 1,25(OH)

Topics: Animals; Bone Density; Disease Models, Animal; Kidney; Male; Nephrectomy; Phosphates; Pyrimidines; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Serotonin; Sodium-Phosphate Cotransporter Proteins, Type II; Tryptophan Hydroxylase

LP533401 is an inhibitor of tryptophan hydroxylase 1, which regulates serotonin production in the gut. Previous work indicates that LP533401 has an anabolic effect in bone. Thus, we hypothesized that inhibition of gut serotonin production may modulate the host response in periodontal disease. In this study, we aimed to analyze the effects of LP533401 in a rat periodontitis model to evaluate the role of gut serotonin in periodontitis pathophysiology.. Twenty-four rats were divided into three groups: treated group (T: ligature-induced periodontal disease and LP533401, 25 mg/kg/d) by gavage; ligature group (L: ligature-induced periodontal disease only); and control group (C: without ligature-induced periodontal disease). After 28 d, radiographic alveolar bone support was measured on digital radiographs, and alveolar bone volume fraction, tissue mineral density and trabeculae characteristics were quantified by microcomputed tomography in the right hemi-mandible. Left hemi-mandibles were decalcified and alveolar bone loss, attachment loss and area of collagen in the gingiva were histologically analyzed.. Significant difference between the L and C groups was found, confirming that periodontal disease was induced. We observed no difference between the T and L groups regarding alveolar bone destruction and area of collagen.. LP533401 (25 mg/kg/d) for 28 d does not prevent bone loss and does not modulate host response in a rat model of induced periodontal disease.

Topics: Alveolar Bone Loss; Animals; Collagen; Disease Models, Animal; Gingiva; Ligation; Male; Mandible; Periodontal Attachment Loss; Periodontal Diseases; Periodontitis; Pyrimidines; Rats; Rats, Wistar; Serotonin; X-Ray Microtomography

In a proof-of-concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy-induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy-induced bone loss in aged mice. It also cures the low bone mass of Lrp5-deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone-loss disorders.

Topics: Aging; Alendronate; Animals; Bone and Bones; Bone Resorption; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastrointestinal Tract; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Mice, Inbred C57BL; Organ Size; Osteoporosis; Ovariectomy; Phenotype; Pyrimidines; Serotonin; Time Factors; Treatment Outcome; Tryptophan Hydroxylase