Thymus-derived lymphocytes and their interactions with macrophages are required for the production of osteoclast-activating factor in the mouse.

Abstract

A bone-resorbing factor, comparable to the osteoclast-activating factor (OAF) produced from peripheral blood leukocytes, is shown to be produced by murine spleen cells activated with the T-cell mitogen Con A. Murine OAF is demonstrated here as being a product of the interaction between thymus-derived T lymphocytes and macrophages. Activation (PTH) or prostaglandin E (PGE) and is not extracted by lipid solvents, therefore excluding both PGE and metabolites of vitamin D, which are also potent stimulators of bone resorption (4,5). Human OAF has been reported to have a molecular size range from 9 (6) to 25 kilodaltons (4, 5); another molecular size species of <3.5 kilodaltons has also been reported (7).OAF production has been linked with increased bone resorption and bone loss in a number of human pathological processes, such as periodontal disease (8), multiple myeloma, lymphosarcoma, and other types of cancer (9, 10). OAF activity has also been demonstrated in supernatants from cultures of tumor cell lines of lymphoid origin (11), activated human tonsil cells (6), and activated mouse spleen cells (12), therefore demonstrating the ability of a number of lymphoid tissues and cell lines to produce such a factor. The production of OAF requires the presence and interaction of lymphocytes and macrophages (3, 13) and this factor has consequently been classified among the lymphokines (14,15). Further identification of the specific cell types involved in OAF production is still lacking and, more specifically, controversy still exists as to whether, under normal conditions, it is a T-or a B-lymphocyte product (14) (or both) and whether it might play a role in the local regulation of bone remodeling.In this report, we have approached the problem of identifying the cell type(s) involved in OAF production by using normal mouse spleen cells cultured in vitro because (i) this organ contains the three major immunocompetent cell types-i.e., T lymphocytes (30%), B lymphocytes (50%), and macrophages (10%); (ii) monoclonal antibodies directed against antigens specific for certain cell types are available and well characterized; and (iii) the approach of the role of local OAF production in the regulation of normal bone remodeling required the use of normal, nontransformed cell sources.The results of our studies suggest that (i) OAF production by normal mouse spleen cells requires the presence and interaction of Thy-1+ T lymphocytes and Ia' macrophages;(ii) B lymphocytes, cultured in the presence of Con A or activated with lipopolysaccaride (LPS), in the presence or absence of macrophages, do not produce detectable amounts of OAF activity; (iii) the presence of B lymphocytes in Con A-activated spleen cell cultures does not alter OAF production by T lymphocytes-macrophage interaction; and (iv) macrophages cocultured with Con A or activated with LPS do not produce detectable amounts of bone-resorbing activity. MATERIALS AND METHODSMice. C57BL/6J, C3H/DiSn, C3H/HeJ, and C3H/HeSn mice were obtained from The Jackson Laboratory. ...

Different inhibitory actions of cyclosporine A and cyclosporine A-acetate on lipopolysaccharide-, interleukin 1-, 1,25 dihydroxyvitamin D3- and parathyroid hormone-stimulated calcium and lysosomal enzyme release from mouse calvariain vitro

“…Macrophages produce two different molecular forms, IL-I alpha and IL-1 beta [7]. IL-1 beta has a high degree of sequence homology with the previously described osteoclast activating factor OAF [8] which is the product of an interaction between T cells and macrophages [9]. The production of OAF by murine spleen cells could be blocked by CsA [10].…”

The Interstitial Mechanisms of Regulation of Cell Growth and the Role of the Immune System: A New Immune Theory of Aging

“…It was shown also that signs of bone tissue growth -osteopetrosis, are corrected by transfer of lymphocytes from healthy animals; moreover, parathyroid hormone, which is specific for osteoclasts, produces the effect through T-lymphocytes, which have receptors to this hormone unlike the osteoclasts. 28,29 General growth inhibition, e.g., dwarfism in mice, can be prevented by the transfer of lymphocytes from healthy animals; and T-lymphocytes have receptors to the growth hormone and their number increases in the period of the animals' growth. 30 There is a known paradox of "nude" mice, which contradicts the theory of tumor supervision (tumor supervision was thought to be the main evolutionary factor in lymphoid system development): the incidence of spontaneous and induced tumors in thymus-free mice is decreased rather than increased.…”

Immunological Response to Post-trauma Bone Remodeling

“…It has also been established that lack of B lymphocytes can lead to higher bone formation in mice. [18][19][20] A study had demonstrated an higher mRNA expression of several genes from FH and SF cells than those in peripheral blood (e.g. osteogenic SSP1, IL-8, CXCR4).…”

“…16,17 Progress has been made in understanding the link between adaptive and innate immune system in bone, with emphasis on osteoclasts. 18,19 The function of the adaptive immune system in fracture healing is less understood. Effector cells of the adaptive immune system are lymphocytes.…”