Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation.

Abstract

Osteopetrosis is a disease of bone resorption that may be inherited with m a n y separate genes in various m a m m a l i a n species (1, 2). There are four distinct mutations in the mouse that can individually result in this disorder: osteopetrotic (op) (3), microopthalmic (mi) (4), gray-lethal (gl) (5), and osteosclerotic (oc) (6). A major advance in our understanding of osteopetrosis was provided by the experiments of Walker (7-9), demonstrating the ability of normal hemopoietic cells to cure this disorder in mi/mi and gl/gl mice. Additionally, it was shown that spleen cells from these mutants transfer the disease into irradiated normal littermate recipients (8, 9). The response of other murine osteopetrotic m u t a n t s in transplantation assays remains unknown. At the cellular level, osteopetrosis is a disease of a functionally a n d / o r quantitatively a b n o r m a l osteoclast (1, 10), The osteoclast is a multinuclear cell that is most p r o b a b l y formed through a fusion of cells of the m o n o c y t e -m a c r o p h a g e lineage (11). Therefore, the osteoclast belongs to the progeny of the hemopoietic stem cell (HSC) 1 (12, 13), and this explains the positive response of mi/mi and gl/gl mice to transplants of hemopoietic cells. This cure of osteopetrosis by hemopoietic grafts is a more general p h e n o m e n o n and was recently observed also in juvenile osteopetrosis in man (14, 15) and in two rat mutants: ia/ia (16) and op/op (17). Studies (18) in op rat additionally linked osteopetrosis with abnormalities in the T lymphocyte system. O n the other hand, the osteopetrosis in tl/tl rat failed to respond to the bone marrow transplant (19), suggesting that the p r i m a r y lesion in this m u t a n t resides beside the hemopoietic tissue, presumably in the hemopoietic microenvironment (HM). The H M is m a d e by stromal tissue of bones and spleen, histogenetically different from the hemopoietic system and largely derived from cells with fibroblast-like morphology (20). The classic example of the disorder of H M is a n e m i a in S1/S1 d mice, which is * Supported in part by a grant from the Polish Academy of Sciences to W. Wiktor-Jedrzeiczak , and by the Naval Medical Research and Development Command. The opinions and assertions contained herein are the private ones of the writers and are not to be construed as official or reflecting the views of the U. S. Navy Department or the naval service at large. The experiments reported herein were conducted according to the principles set forth in the current edition of the "Guide for the Care and Use

Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in TRAF6‐deficient mice

“…Although CD40-deficient mice do not exhibit the reduction of immature B cells in bone marrow (Kawabe et al 1994), possible defect in CD40 signalling in TRAF6 ¹/¹ mice could be involved in this apoptosis in combination with defect in unknown receptor that also requires TRAF6 for signalling. Alternatively, the observed defect in B cell development could be due to the impaired bone marrow environment as a consequence of osteopetrosis as in the case of c-fos ¹/¹ mice (Okada et al 1994) and op/op mice (Wiktor-Jedrzejckaz et al 1982). In contrast to the normal thymocyte development in TRAF6 ¹/¹ mice, the development of CD3/CD4/CD8 triple negative CD44 ¹ CD25 þ precursors to CD44 ¹ CD25 ¹ thymocytes was blocked in ODF ¹/¹ mice (Kong et al 1999).…”

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

“…The role of M-CSF in monocyte development, however, is more controversial. Early studies reported that the number of monocytes was reduced in the blood of M-CSF-deficient mice probably because of a deficiency of osteoclasts that are required to maintain a functional BM microenvironment (2,4,10,(26)(27)(28). A later study showed that M-CSF was critical for the survival of circulating monocytes in the periphery (29).…”

“…However, follow-up studies showed that there is no reduction in circulating monocytes, and the selective deficiency in tissue macrophage populations is corrected as CSF1 op /CSF1 op mice age (6,7). Because of the conflicting results, whether M-CSF functions in monocyte production in the BM or at the transition of monocyte into macrophage in the tissues is still controversial (3,4,6,(8)(9)(10). GM-CSF was identified to stimulate the generation of granulocyte and macrophage colonies when added to the BM cell culture in vitro.…”

Monocytes and Macrophages in Cancer: Development and Functions

“…Monopoiesis is tightly regulated by microenvironmental cues, modulating gene expression in developing cells and leading to the often irreversible, phenotypic and functional changes associated with hematopoietic differentiation. Although the key role of cytokines, such as macrophage colony-stimulating factor (M-CSF), granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), within this developmental niche has been intensively studied [12][13][14], the impact of other niche components, like immobilized factors on stromal cells or extracellular matrix (ECM) components, on monopoiesis remains still unclear. Early-phase monopoiesis proceeds via distinct proliferative progenitor stages, such as common myeloid progenitors (CMP) and granulocyte/macrophage progenitors (GMP) [15], to the macrophage dendritic cell progenitor (MDP) [12,16], which serves as a common precursor for monocytes, macrophages and dendritic cells (DCs).…”