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. 2011 Jan 11;108(2):768-73.
doi: 10.1073/pnas.1013492108. Epub 2010 Dec 27.

Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand (VSports手机版)

Jau-Yi Li  1 , Hesham Tawfeek, Brahmchetna Bedi, Xiaoying Yang, Jonathan Adams, Kristy Y Gao, Majd Zayzafoon, M Neale Weitzmann, Roberto Pacifici
Affiliations

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

Jau-Yi Li et al. Proc Natl Acad Sci U S A. .

Abstract

The bone loss induced by ovariectomy (ovx) has been linked to increased production of osteoclastogenic cytokines by bone marrow cells, including T cells and stromal cells (SCs). It is presently unknown whether regulatory interactions between these lineages contribute to the effects of ovx in bone, however. Here, we show that the T-cell costimulatory molecule CD40 ligand (CD40L) is required for ovx to expand SCs; promote osteoblast proliferation and differentiation; regulate the SC production of the osteoclastogenic factors macrophage colony-stimulating factor, receptor activator of nuclear factor-κB ligand, and osteoprotegerin; and up-regulate osteoclast formation. CD40L is also required for ovx to activate T cells and stimulate their production of TNF. Accordingly, ovx fails to promote bone loss and increase bone resorption in mice depleted of T cells or lacking CD40L VSports手机版. Therefore, cross-talk between T cells and SCs mediated by CD40L plays a pivotal role in the disregulation of osteoblastogenesis and osteoclastogenesis induced by ovx. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Effects (mean ± SEM) of ovx on bone structure, bone resorption, and in vitro OC formation in T cell-depleted mice, CD40L−/− mice, and WT mice treated with the anti-CD40L Ab MR-1. (A) Representative cross-sectional reconstructions of the femur and trabecular structural indices in WT mice treated with irrelevant Ab (Irr. Ig) or anti-CD4 and anti-CD8 Abs (CD4/8 Ig) (n = 10 mice per group). BV/TV, trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular space (Tb.Sp) are shown. (B) Representative cross-sectional reconstructions of the femur and trabecular structural indices in WT and CD40L−/− mice (n = 16 mice per group). (C) Representative cross-sectional reconstructions of the femur and trabecular structural indices in WT mice treated with MR-1 or irrelevant Ab (n = 10 mice per group). (D) Serum levels of CTx, a marker of resorption. *P < 0.05. (E) Number of OCs in cultures of whole BM stimulated with RANKL and M-CSF. *P < 0.05, **P < 0.01, and *** = P < 0.001 compared with the corresponding sham-operated group. #P < 0.05 compared with WT sham-operated mice. aP < 0.05 compared with ovx CD40 irrelevant isotope-matched Ab (Irr. Ig).
Fig. 2.
Fig. 2.
Effects (mean ± SEM) of T cells and ovx on SC cytokine mRNA and SC osteoblastic commitment, proliferation, and differentiation in T cell-depleted mice, CD40L−/− mice, and WT mice treated with the anti-CD40L Ab MR-1. (A) SC proliferation as assessed by pulsing with [3H]thymidine for 18 h. (B) Number of BM SCs. (C) Effect of T cells on the expression of SC cytokine mRNA. *P < 0.05 compared with the respective SC-only group. (D) CFU-ALP formation in BM cultures. The average of the colonies counted in six wells is shown. (E–H) SC expression of mRNA of the OB markers type I collagen (Col1), osteocalcin (Ocn), osterix (Osx), and runx2 (Runx2) (n = 4–5 per group). *P < 0.05, compared with the corresponding sham-operated group.
Fig. 3.
Fig. 3.
Effect (mean ± SEM) of T cells and CD40L on SC osteoclastogenic activity and cytokine secretion. (A) Effect of ovx on the osteoclastogenic activity of SCs from mice treated with irrelevant isotype-matched Ab (Irr. Ig) or anti-CD4 and anti-CD8 Abs (CD4/8 Ig). All cultures were stimulated with PTH (1 nM), an agent that targets SCs. (B) Effect of ovx on the osteoclastogenic activity of SCs from WT and CD40L−/− mice. All cultures were stimulated with PTH (1 nM). (C) Effect of T cells from sham-operated and ovx mice and of CD40L neutralization on the osteoclastogenic activity of SCs. All cultures were stimulated with PTH (1 nM). (D–F) Effect of ovx on the production of M-CSF, RANKL, and OPG by SCs from T cell-depleted mice, CD40L−/− mice, and MR-1–treated mice. *P < 0.05 and **P < 0.01 compared with the corresponding controls. #P < 0.05 compared with the other groups.
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