Depletion of CD4 and CD8 T Lymphocytes in Mice In Vivo Enhances 1,25-Dihydroxyvitamin D3-Stimulated Osteoclast-Like Cell Formation In Vitro by a Mechanism That Is Dependent on Prostaglandin Synthesis

Abstract

To investigate the role of T lymphocytes in osteoclastogenesis, we performed in vivo depletion of CD4 and/or CD8 T lymphocyte subsets and evaluated in vitro osteoclast-like cell (OCL) formation. T lymphocyte depletion (TLD) with mAbs was confirmed 24 h later by flow cytometry. OCL formation was stimulated with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in bone marrow and with recombinant mouse (rm) receptor activator of NF-κB ligand (RANK-L) and rmM-CSF in bone marrow and spleen cell cultures. OCL formation was up to 2-fold greater in 1,25-(OH)2D3-stimulated bone marrow cultures from TLD mice than in those from intact mice. In contrast, TLD did not alter OCL formation in bone marrow or spleen cell cultures that were stimulated with rmRANK-L and rmM-CSF. The effects of TLD seemed to be mediated by enhanced PG synthesis, because the PGE2 concentration in the medium of 1,25-(OH)2D3-stimulated bone marrow cultures from TLD mice was 5-fold higher than that in cultures from intact mice, and indomethacin treatment abolished the stimulatory effect of TLD on OCL formation. There was a 2-fold increase in RANK-L expression and an almost complete suppression of osteoprotegerin expression in 1,25-(OH)2D3-stimulated bone marrow cultures from TLD mice compared with those from intact mice. Although there was a small (20%) increase in IL-1α expression in 1,25-(OH)2D3-stimulated bone marrow cultures from TLD mice, TLD in mice lacking type I IL-1R and wild-type mice produced similar effects on OCL formation. Our data demonstrate that TLD up-regulates OCL formation in vitro by increasing PG production, which, in turn, produces reciprocal changes in RANK-L and osteoprotegerin expression. These results suggest that T lymphocytes influence osteoclastogenesis by altering bone marrow stromal cell function.

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis

“…Indirect evidence in the literature also supports our conclusions that activated T cells inhibit osteoclastogenesis, and the present study provides a potential mechanism. For example, vitamin D3 stimulation of osteoclasts in vitro is enhanced by T-cell depletion (30); removing T cells would also remove any OX40 expressed by them. CD8 + T cells are also antiosteoclastogenic (15,31) and express high levels of OX40 during infections (32-34) associated with arthritic disease flare (35).…”

Increased bone resorption and osteopenia are a part of the lymphoproliferative phenotype of mice with systemic over-expression of interleukin-7 gene driven by MHC class II promoter

“…Another downstream cytokine in IL-7 over-expressing environment could be RANKL, the key osteoclastogenic factor that binds to its RANK receptor on OCL precursors [15] and is able to induce CD45R + cell proliferation in combination with IL-7 [23]. RANKL, shown to increase with IL-7 stimulation of T lymphocytes [15], mediates bone resorption together with tumor necrosis factor-α in IL-7 treated mice [18]. As we added soluble RANKL and M-CSF in culture, the contribution of increased RANKL expression in stromal cells or T lymphocytes could not be assessed.…”

Estrogen deficiency and bone loss: an inflammatory tale

“…In the absence of strong activation signals, T cells appear to repress OC formation (47), but the relevance of this phenomenon in vivo has not been established. In contrast, activated T cells play a key role in the regulation of OC formation through increased production of RANKL and TNF (48)(49)(50).…”