title: Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass.
abstract: CD74 is a type II transmembrane protein that can act as a receptor for macrophage migration inhibitory factor (MIF) and plays a role in MIF-regulated responses. We reported that MIF inhibited osteoclast formation and MIF knockout (KO) mice had decreased bone mass. We therefore examined if CD74 was involved in the ability of MIF to alter osteoclastogenesis in cultured bone marrow (BM) from wild-type (WT) and CD74-deficient (KO) male mice. We also measured the bone phenotype of CD74 KO male mice. Bone mass in the femur of 8-week-old mice was measured by micro-computed tomography and histomorphometry. Bone marrow cells from CD74 KO mice formed 15% more osteoclast-like cells (OCLs) with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) (both at 30 ng/mL) compared to WT. Addition of MIF to WT cultures inhibited OCL formation by 16% but had no effect on CD74KO cultures. The number of colony forming unit granulocyte-macrophage (CFU-GM) in the bone marrow of CD74 KO mice was 26% greater than in WT controls. Trabecular bone volume (TBV) in the femurs of CD74 KO male mice was decreased by 26% compared to WT. In addition, cortical area and thickness were decreased by 14% and 11%, respectively. Histomorphometric analysis demonstrated that tartrate-resistant acid phosphatase (TRAP)(+) osteoclast number and area were significantly increased in CD74 KO by 35% and 43%, respectively compared to WT. Finally, we examined the effect of MIF on RANKL-induced-signaling pathways in bone marrow macrophage (BMM) cultures. MIF treatment decreased RANKL-induced nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and c-Fos protein in BMM cultures by 70% and 41%, respectively. Our data demonstrate that CD74 is required for MIF to affect in vitro osteoclastogenesis. Further, the bone phenotype of CD74 KO mice is similar to that of MIF KO mice. MIF treatment of WT cultures suppressed RANKL-induced activator protein 1 (AP-1) expression, which resulted in decreased osteoclast differentiation in vitro. We propose that CD74 plays a critical role in the MIF inhibition of osteoclastogenesis.
authors.affiliation: UCONN Center on Aging, University of Connecticut Health Center, Farmington, CT 06030-1835, USA.
authors.forename: Se Hwan
authors.initials: SH
authors.lastname: Mun
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Won
authors.forename: Paula
authors.initials: P
authors.lastname: Hernandez
authors.forename: Hector Leonardo
authors.initials: HL
authors.lastname: Aguila
authors.forename: Sun-Kyeong
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D017353:Gene Deletion; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D050778:NFATC Transcription Factors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D018808:Transcription Factor AP-1 / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008263:Macrophage Migration-Inhibitory Factors; D050778:NFATC Transcription Factors; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1; C045084:invariant chain; C033184:macrophage migration inhibitory factor receptor; D000072000:NF-KappaB Inhibitor alpha; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase