Aluminium-induced bone disease in uremic rats: effect of deferoxamine.
We have previously established a rat model of chronic uremia, which is suitable to investigate the effect of various treatment modalities on renal osteodystrophy [1]. After four months subsequent to 5/6 nephrectomy, some animals were treated by gavage for 9 weeks with tap water (controls), or with aluminium (Al-citrate) 3 x 25 mg/week/kg b.wt +/- subsequent deferoxamine (DFO) 3 x 50 mg/week/kg b.wt. for 4 weeks. At termination of the study, serum clinical chemistry, femoral chemical composition and mechanical properties, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC) and phospholipase C (PLC) activities, cross-sectional femoral area, as well as bone histomorphometry, were analyzed. Animals given Al displayed moderately enhanced serum Al and bone Al accumulation, however, DFO-treatment did not fully alleviate bone Al retainment. A small increase in serum PTH was seen in all animals rendered uremic. Furthermore, a marked fall in serum alkaline phosphatase (ALP) below normal controls was observed in Al +/- DFO-treated animals compared with uremic controls. The uremic condition led to reduced femoral ratios of hydroxyproline (HYP) over Ca(2+) and phosphate (P(i)), while Al-intoxication alone enhanced femoral Hyp contents above values seen for normal controls. The protracted ureamia caused a deterioration of long bone resilience and brittleness, however, Al +/- DFO-treatment seemed to normalize the latter. Contrastingly, Al +/- DFO-gavage enhanced time to fracture. Uremic rats intoxicated with Al showed a complete loss of calvarial PTH-sensitive AC and PLC activities. DFO-treatment normalized PTH-elicited PLC, while PTH-susceptible AC remained super-normal. Al apparently exerts a long term down-regulation of both PTH-sensitive signaling systems as evidenced by studies of rat UMR 106 osteosarcoma cells in culture. The uremic condition enhanced endosteal bone resorption as shown by femoral shaft dimension analysis, while Al +/- DFO-treatment insignificantly reversed the condition. Finally, histomorphometrical analyses showed that DFO-administration tended to normalize aberrant trabecular bone volume, while rectifying both bone resorption and degree of mineralization. In conclusion, we assert that Al-intoxication hampers both processes (i.e. formation and resorption) of bone turnover, and that DFO-treatment to a certain extent prevents the uremia- and Al-induced bone disease in rats.
Jablonski
G
G
Institute for Surgical Research, The National Hospital, Rikshospitalet, Oslo, Norway.
Klem
K H
KH
Danielsen
C C
CC
Mosekilde
L
L
Gordeladze
J O
JO
D000262:Adenylyl Cyclases / Q000378:metabolism; D000535:Aluminum / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001696:Biomechanical Phenomena; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000517:prevention & control; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D003676:Deferoxamine / Q000494:pharmacology*; D005260:Female; D010018:Osteomalacia / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017262:Siderophores / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism; D014511:Uremia / Q000150:complications*
D010281:Parathyroid Hormone; D017262:Siderophores; D000535:Aluminum; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D003676:Deferoxamine