title: The toothless osteopetrotic rat has a normal vitamin D-binding protein-macrophage activating factor (DBP-MAF) cascade and chondrodysplasia resistant to treatments with colony stimulating factor-1 (CSF-1) and/or DBP-MAF.
abstract: The osteopetrotic rat mutation toothless (tl) is characterized by little or no bone resorption, few osteoclasts and macrophages, and chondrodysplasia at the growth plates. Short-term treatment of tl rats with colony-stimulating factor-1 (CSF-1) has been shown to increase the number of osteoclasts and macrophages, producing dramatic resolution of skeletal sclerosis at some, but not all, sites. Defects in production of vitamin D-binding protein-macrophage activating factor (DBP-MAF) have been identified in two other independent osteopetrotic mutations of the rat (op and ia), and two in the mouse (op and mi), in which macrophages and osteoclasts can be activated by the administration of exogenous DBP-MAF. The present studies were undertaken to examine the histology and residual growth defects in tl rats following longer CSF-1 treatments, to investigate the possibility that exogenous DBP-MAF might act synergistically with CSF-1 to improve the tl phenotype, and to assess the integrity of the endogenous DBP-MAF pathway in this mutation. CSF-1 treatment-with or without DBP-MAF-induced resorption of metaphyseal bone to the growth plate on the marrow side, improved slightly but did not normalize long bone growth, and caused no improvement in the abnormal histology of the growth plate. Injections of lysophosphatidylcholine (lyso-Pc) to prime macrophage activation via the DBP-MAF pathway raised superoxide production to similar levels in peritoneal macrophages from both normal and mutant animals, indicating no defect in the DBP-MAF pathway in tl rats. Interestingly, pretreatments with CSF-1 alone also increased superoxide production, although the mechanism for this remains unknown. In summary, we find that, unlike other osteopetrotic mutations investigated to date, the DBP-MAF pathway does not appear to be defective in the tl rat; that additional DBP-MAF does not augment the beneficial skeletal effects seen with CSF-1 alone; and that the growth plate chondrodystrophy seen in this mutation is unaffected by either molecule. Thus, the tl mutation intercepts the function of a gene required for both normal endochondral ossification and bone resorption, thereby uncoupling the coordination of skeletal metabolism required for normal long bone growth.
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester 01665, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Odgren
authors.forename: S N
authors.initials: SN
authors.lastname: Popoff
authors.forename: F F
authors.initials: FF
authors.lastname: Safadi
authors.forename: C A
authors.initials: CA
authors.lastname: MacKay
authors.forename: A
authors.initials: A
authors.lastname: Mason-Savas
authors.forename: M F
authors.initials: MF
authors.lastname: Seifert
authors.forename: S C
authors.initials: SC
authors.lastname: Marks
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D004359:Drug Therapy, Combination; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D016215:Macrophage-Activating Factors / Q000502:physiology / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D010022:Osteopetrosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D011859:Radiography; D051381:Rats; D011922:Rats, Mutant Strains; D013481:Superoxides / Q000378:metabolism; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D014809:Vitamin D-Binding Protein / Q000502:physiology / Q000627:therapeutic use
chemical_list: D008244:Lysophosphatidylcholines; D016215:Macrophage-Activating Factors; D014809:Vitamin D-Binding Protein; C101908:vitamin D-binding protein-macrophage activating factor; D013481:Superoxides; D016173:Macrophage Colony-Stimulating Factor