Patientswithbenign familial hypocalciuric hypercalcemia (FHH) areheterozygousforinactivatingmutationsoftheCaSR.Inthesepatients,becauseofcompleteorpartiallossofoneCaSRallele,higherlevelsof[Ca++]arerequiredtosuppressPTHsecretion.Thisresultsinanelevated[Ca++]setpointforPTHsecretion,accountingforthehypercalcemia.TheCaSRisalsoexpressedinthethickascendinglimboftherenaltubule,whereitnormallyinhibitsCa++ reabsorptionwhenbloodCa++ rises.ThehypocalciuriainthefaceofhypercalcemiainFHHisduetothereducedabilityoftheCaSRinthekidneytosenseandrespondtoelevatedblood[Ca++]byincreasingCaexcretion.
Parathyroid hormone–related peptide (PTHrP) isapeptideparacrinehormoneproducedbyseveraladulttissues(skin,hair,breast),whereitmayregulateproliferationanddifferentiation.Italsoplaysaroleinrelaxationofsmoothmuscleinresponsetostretchinbloodvessels,uterus,andbladder.Duringlactation,PTHrPpromotesmaternalboneresorptionandthetransportofcalciumintomilk.Duringdevelopment,PTHrPregulatescalciumtransportacrosstheplacentaandisakeyregulatorofchondrocyteproliferationanddifferentiationinthegrowthplateoflongbones.The30aminoacidsattheN-terminusofPTHrPhavesignificantstructuralhomologywithPTH.PTHrPisnotregulatedbycirculatingCa++ andnormallydoesnotplayaroleinCa/Pihomeostasisinadults.However,certaintumorssecretehighlevelsofPTHrP,whichcauseshypercalcemia of malignancy andsymptomsthatresemblehyperparathyroidism.
Hormonal Regulation of Calcium and Phosphate Metabolism 1,25-(OH)2D3 24,25-(OH)2D3 •Fig. 40.5 Biosynthesisof1,25-dihydroxyvitaminD.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) and to a lesser extent Pi absorption by the small intestine. It also regulates bone remodeling and renal reabsorption of Ca and Pi.
Structure, Synthesis, and Transport of Active Vitamin D Metabolites
Vitamin D3 (also called cholecalciferol) is synthesized via conversion of 7-dehydrocholesterol by ultraviolet B •Fig. 40.6 VitaminDmetabolism.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)7-Dehydrocholesterol Vit D-DBP and Vit D-chylomicron 25(OH) Vit D-DBP Vit D-chylomicron Lymphatic Vit D-DBP 1,25-Dihydroxyvitamin D Portal blood Caval blood Peripheral blood Vitamin D3 Enterocyte Dietary vitamin D3 and vitamin D2 Vit D UV-B Hepatocyte Vit D 25-Hydroxyvitamin D 25-Hydroxylase 24-Hydroxylase 24-Hydroxylase25-Hydroxyvitamin D 24,25-Dihydroxyvitamin D 1, 25-Dihydroxyvitamin D 1,24,25-Trihydroxyvitamin D Biological effects at gut, bone, kidney, etc. 1˜-Hydroxylase (UVB) light in the more basal layers of the skin (Fig. 40.6 ). Chemically, vitamin D3 is a secosteroid in which one of the cholesterol rings is opened (see