ABSTRACT
Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-kappaB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca(2+) diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca(2+) levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6-9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.
Subject(s)
Disease Models, Animal , Glycoproteins/antagonists & inhibitors , Glycoproteins/metabolism , Hyperparathyroidism/metabolism , Kidney Failure, Chronic/metabolism , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/metabolism , Absorptiometry, Photon , Animals , Carrier Proteins/antagonists & inhibitors , Glycoproteins/genetics , Humans , Hyperparathyroidism/etiology , Hyperparathyroidism/pathology , Kidney Failure, Chronic/complications , Male , Membrane Glycoproteins/antagonists & inhibitors , Osteoprotegerin , Parathyroid Hormone/blood , RANK Ligand , Rats , Rats, Sprague-Dawley , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Tumor Necrosis Factor/geneticsABSTRACT
Human recombinant interleukin-1 receptor antagonist (rhIL-1ra), a 17.2 kd protein is currently in clinical trials for the treatment of rheumatoid arthritis (RA). Skin reactions in some patients with RA prompted investigation of a possible pathogenesis involving nonimmunologically mediated mast cell degranulation. Rats injected intradermally with 20 microliters of rhIL-1ra (100 or 200 mg/ml) or the rhIL-1ra vehicle CSEP (10 mmol/L Na-citrate, 0.5 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1% polysorbate 80, 140 mmol/L NaCl, pH 6.5) had marked (15x or 10x, respectively) Evans blue dye permeability increases as compared with rats injected with phosphate-buffered saline solution (PBS) or bovine serum albumin (BSA). The permeability changes were reduced or eliminated by subcutaneous or local treatment with the antihistamine diphenhydramine. Histologic evaluation of skin sections from rats injected intradermally with CSEP or rhIL-1ra in CSEP revealed mast cell degranulation and edema, features not seen in sites injected with PBS or BSA in PBS. Components of the vehicle were investigated individually for their capacity to cause the reaction. Na-citrate (10 mmol/L) induced a greater increase in permeability than did EDTA (0.5 mmol/L) or polysorbate 80 (0.1%), and all produced reactions that were significantly greater than those occurring at PBS-injected sites. Evans blue dye permeability increases after subcutaneous injection of 1 ml of rhIL-1ra (100 mg/ml) in CSEP (with and without diphenhydramine) or rhIL-1ra in PBS were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Cell Degranulation/drug effects , Mast Cells/drug effects , Receptors, Interleukin-1/antagonists & inhibitors , Sialoglycoproteins/pharmacology , Animals , Capillary Permeability/drug effects , Diphenhydramine/pharmacology , Evans Blue/pharmacokinetics , Humans , Interleukin 1 Receptor Antagonist Protein , Male , Mast Cells/physiology , Pharmaceutical Vehicles , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Recombinant Proteins/pharmacology , Sialoglycoproteins/administration & dosage , Sialoglycoproteins/adverse effects , Skin/drug effectsABSTRACT
It is often postulated that a mother's past experiences influence her ability to function as a parent. If those past experiences involve her as a victim of abuse, what lies ahead for her offspring? We studied 59 mothers of children referred for nonorganic failure to thrive (NOFTT) to the University of Colorado Health Sciences Center and compared their abuse history with a group of 131 mothers of children with normal growth. The mothers of NOFTT children were younger but of the same socioeconomic groups as the comparison mothers. Mothers of NOFTT children had a significantly higher history of abuse when compared to the comparison group p < 0.001. A surprising 80% of mothers of NOFTT children reported they were victims of abuse. We alert clinicians to the likelihood that mothers of children with NOFTT may be victims of abuse and that successful treatment of the child depends upon treatment of the mother-child dyad.