B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo.
Bone homeostasis is regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclastogenesis is controlled by the ratio of receptor activator of NF-kappaB ligand (RANKL) relative to its decoy receptor, osteoprotegerin (OPG). The source of OPG has historically been attributed to osteoblasts (OBs). While activated lymphocytes play established roles in pathological bone destruction, no role for lymphocytes in basal bone homeostasis in vivo has been described. Using immunomagnetic isolation of bone marrow (BM) B cells and B-cell precursor populations and quantitation of their OPG production by enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), cells of the B lineage were found to be responsible for 64% of total BM OPG production, with 45% derived from mature B cells. Consistently B-cell knockout (KO) mice were found to be osteoporotic and deficient in BM OPG, phenomena rescued by B-cell reconstitution. Furthermore, T cells, through CD40 ligand (CD40L) to CD40 costimulation, promote OPG production by B cells in vivo. Consequently, T-cell-deficient nude mice, CD40 KO mice, and CD40L KO mice display osteoporosis and diminished BM OPG production. Our data suggest that lymphocytes are essential stabilizers of basal bone turnover and critical regulators of peak bone mass in vivo.
Li
Yan
Y
Division of Endocrinology & Metabolism & Lipids, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Toraldo
Gianluca
G
Li
Aimin
A
Yang
Xiaoying
X
Zhang
Hongying
H
Qian
Wei-Ping
WP
Weitzmann
M Neale
MN
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015519:Bone Density / Q000276:immunology; D001862:Bone Resorption / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010006:Osteoblasts / Q000276:immunology; D010010:Osteoclasts / Q000276:immunology; D010012:Osteogenesis / Q000276:immunology*; D010024:Osteoporosis / Q000276:immunology; D053244:Osteoprotegerin / Q000276:immunology; D053245:RANK Ligand / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000276:immunology
D019013:CD40 Antigens; D053244:Osteoprotegerin; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D053319:Tumor Necrosis Factor Decoy Receptors; D023201:CD40 Ligand