title: Increased serum enzyme levels associated with kupffer cell reduction with no signs of hepatic or skeletal muscle injury.
abstract: Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of serum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury. Specifically, neutralizing M-CSF activity via a novel human monoclonal antibody reduced the CD14(+)CD16(+) monocyte population, depleted KCs, and increased aspartate aminotransferase and creatine kinase serum enzyme levels in cynomolgus macaques. In addition, the treatment of rats with clodronate liposomes depleted KCs and led to increased serum enzyme levels, again without evidence of tissue injury. Finally, in the osteopetrotic (Csf1(op)/Csf1(op)) mice lacking functional M-CSF and having reduced levels of KCs, the levels of serum enzymes are higher than in wild-type littermates. Together, these findings support a mechanism for increases in serum enzyme levels through M-CSF regulation of tissue macrophage homeostasis without concomitant histopathological changes in either the hepatic or skeletal system.
authors.affiliation: Department of Biotherapeutics Research & Development, Pfizer Worldwide Research and Development, Cambridge, MA 02140, USA. zaher.radi@pfizer.com
authors.forename: Zaher A
authors.initials: ZA
authors.lastname: Radi
authors.forename: Petra H
authors.initials: PH
authors.lastname: Koza-Taylor
authors.forename: Rosonald R
authors.initials: RR
authors.lastname: Bell
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Obert
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Runnels
authors.forename: Jean S
authors.initials: JS
authors.lastname: Beebe
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lawton
authors.forename: Seth
authors.initials: S
authors.lastname: Sadis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D008252:Macaca fascicularis; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D010022:Osteopetrosis / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; D004002:Clodronic Acid; D016173:Macrophage Colony-Stimulating Factor; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase