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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3839-3848.
Prepublished online as a Blood First Edition Paper on January 3, 2007; DOI 10.1182/blood-2006-07-037994.
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IMMUNOBIOLOGY
B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo
Yan Li1,
Gianluca Toraldo2,
Aimin Li1,
Xiaoying Yang1,
Hongying Zhang1,
Wei-Ping Qian1, and
M. Neale Weitzmann1
1 Division of Endocrinology & Metabolism & Lipids, Emory University School of Medicine, Atlanta, GA;
2 Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy
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- B 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.
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