T Lymphocyte–Deficient Mice Lose Trabecular Bone Mass With Ovariectomy

Abstract

We examined OVX-induced bone loss in three TLD mouse models. In TLD mice, OVX caused trabecular bone loss equivalent to that of WT. In contrast, cortical bone loss with OVX was variable. We conclude that T lymphocytes do not influence OVX-induced trabecular bone loss. Introduction:We examined ovariectomy (OVX)-induced bone loss in three T lymphocyte-deficient (TLD) mouse models: nude mice, recombination activating gene 2-deficient (RAG2 KO) mice, and ⌻ cell receptor ␣ chain-deficient (TCR␣ KO) mice. Materials and Methods: Bone mass was examined by DXA, CT, and histomorphometry. We also examined the effect of OVX on T lymphocytes in the bone marrow and spleens of wildtype (WT) mice and on in vitro osteoclastogenesis and colony forming unit-granulocyte macrophage (CFU-GM) activity in the bone marrow of WT and nude mice. Results: In WT mice, OVX did not alter T lymphocyte number in the bone marrow but did increase T lymphocytes in the spleen. Comparison of bone mass in nude, RAG2 KO, and TCR␣ KO mice with WT as measured by DXA showed decreased femoral bone mass in nude mice and increased vertebral bone mass in RAG2 KO mice. In TCR␣ KO mice, femoral, tibial, and vertebral bone mass were decreased. In vertebrae and long bones, bone loss with OVX was consistently present in WT mice but variably present in TLD mice as measured by DXA. In contrast, CT and histomorphometry showed similar trabecular bone loss after OVX in all mice. However, femoral cortical bone loss occurred only in WT and RAG2 KO mice. OVX produced similar trabecular bone loss in WT and TCR␣ ⌲⌷ mice and also induced cortical bone loss in both. Histomorphometry showed that TRACP + area in bones was increased by OVX in femurs from both WT and nude mice as was in vitro osteoclast-like cell formation and CFU-GM activity. Conclusions: These results show that OVX caused similar trabecular bone loss in both WT and TLD mice. The ability of DXA and measurement of cortical bone loss to show OVX-induced effects on bone mass was variable. It seems that T lymphocytes are not critical for OVX-induced trabecular bone loss in these mouse models.

Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand

“…An independent confirmation of the role of T cells was provided by Yamaza et al (26), who reported that ovx fails to induce bone loss in nude mice and WT mice in which T-cell activation was blocked by aspirin. By contrast, Lee et al (48) showed that nude mice are protected against the loss of cortical but not trabecular bone induced by ovx. In the same study, other strains of T-cell and T-and B-cell deficient mice were found to lose either trabecular or cortical bone after ovx (48).…”

“…By contrast, Lee et al (48) showed that nude mice are protected against the loss of cortical but not trabecular bone induced by ovx. In the same study, other strains of T-cell and T-and B-cell deficient mice were found to lose either trabecular or cortical bone after ovx (48). The discrepancy between our reports (17,24,25,43,44) and that of Lee et al (48) is likely explained by differences in the experimental design, the lack of B cells in some models, and compensation mechanisms.…”

Receptor Activator of Nuclear Factor κB Ligand (RANKL) Protein Expression by B Lymphocytes Contributes to Ovariectomy-induced Bone Loss

“…T lymphocytes are thought to be involved in the bone loss caused by ovariectomy in mice (15), although some studies have been unable to demonstrate a requirement for this cell type (50). The major mechanism is thought to be increased production of T cells that produce TNF␣ (51), with a possible additional contribution of RANKL produced by T cells.…”

Osteoimmunology: from mice to humans

“…1 During estrogen deficiency the immune response is altered and, in particular, T cells become more active and able to produce inflammatory and pro-osteoclastogenic cytokines such as TNFa and RANKL. Despite some inverse reports, 34,35 the main body of literature firmly supports the essential role of activated T cells in regulating bone loss induced by estrogen deficiency, 5,[36][37][38] both in animal models and in humans.…”