Molecular mechanisms of secondary hyperparathyroidism.
Secondary hyperparathyroidism is a frequent complication of chronic renal failure (CRF) and a major factor in the pathogenesis of renal osteodystrophy. A high serum phosphate, decreased levels of serum 1,25(OH)2D3 and the subsequently low serum calcium are the major metabolic abnormalities in CRF, which lead to the secondary hyperparathyroidism. At the level of parathyroid hormone (PTH) secretion there is insensitivity to the ambient serum calcium. PTH mRNA levels are increased by a post-transcriptional mechanism that involves the binding of PT cytosolic proteins to the PTH mRNA 3'-untranslated region (UTR). In a dietary model of secondary hyperparathyroidism due to hypocalcemia there is increased binding of parathyroid proteins to the 3'-UTR and decreased degradation as determined by an in vitro degradation assay. Changes in serum phosphate also dramatically regulate PTH mRNA stability. There is also regulation at the level of PT cell proliferation. PT cell proliferation is increased by experimental hypocalcemia or hyperphosphatemia and decreased by hypophosphatemia and administered 1,25(OH)2D3. The understanding of the molecular mechanisms involved in the genesis of secondary hyperparathyroidism will allow the design of new effective strategies in the management of this troubling condition.
Silver
J
J
Minerva Center for Calcium and Bone Metabolism, Hadassah Hospital and Hebrew University, Hadassah Medical School, Jerusalem, Israel. silver@cc.huji.ac.il
Kilav
R
R
Sela-Brown
A
A
Naveh-Many
T
T
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002455:Cell Division; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000235:genetics*; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010281:Parathyroid Hormone / Q000235:genetics; D010710:Phosphates / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology
D020413:3' Untranslated Regions; D010281:Parathyroid Hormone; D010710:Phosphates; D011506:Proteins; D012333:RNA, Messenger; D014807:Vitamin D; D012313:RNA; D002118:Calcium