Bone modulation in sustained hematopoietic stimulation in mice

Abstract

To understand the etiology of bone modulation and hypercalcemia observed in granulocytosis of a tumor-bearing animal model and to gain insight into the implication of sustained hematopoietic stimulation on the bone tissue, in vivo responses of normal mouse hematopoietic and bone tissues to long-term injections of recombinant human and murine granulocyte colony-stimulating factor (G-CSF), murine granulocyte- macrophage CSF (GM-CSF), and human erythropoietin were quantitatively analyzed. Osteoclast activation was estimated by the osteoclast- endosteal ratio, determined by morphometric analyses of femoral sections. Medullary and bone areas were measured on transverse ground bone sections of the tibia. Recombinant murine G-CSF provoked marked granulocytosis associated with significant increases in the number of marrow granulocytes and their progenitors, and caused expansion of granulopoietic marrow into fatty marrow. The bone of G-CSF-treated mice showed a significant increase in endosteal osteoclast numbers with medullary area enlargement and a reduction in the bone thickness; indicative of endosteal bone resorption. Although GM-CSF had little effect on granulopoiesis, it caused peritoneal macrophages to increase and induced similar bone changes as those observed in G-CSF treatment. Enhanced erythropoiesis stimulated by erythropoietin was also associated with evidence of endosteal bone resorption. Bone changes induced by these growth factors were not associated with hypercalcemia. These animal studies document association of bone modulation in sustained stimulation of hematopoiesis, and implicate important physiologic effects of hematopoietic growth factors on skeletal tissue in vivo.

Human Bone Marrow Adipocytes Block Granulopoiesis Through Neuropilin-1-Induced Granulocyte Colony-Stimulating Factor Inhibition

“…This observation was in agreement with our previous data on the MS5 cell line, which lost its capacity to sustain granulopoiesis after differentiation into adipocytes [31]. GM-CSF was constitutively expressed by FLFCs but increased in cocultures with CD34 ϩ progenitors, which is probably the reason why a few immature granulocytes differentiate in culture [57,58]. This growth factor has also been demonstrated in freshly isolated BM adipocytes (data not shown), as well as in BM preadipocytes [59].…”

Granulocyte Colony-Stimulating Factor Induces Osteoblast Apoptosis and Inhibits Osteoblast Differentiation

“…Previous studies have established that chronic treatment with G-CSF leads to increased osteoclast number and activity. (4)(5)(6)23,24) Although there is evidence that G-CSF can directly activate the osteoclast lineage, (8) the potent suppressive effect of G-CSF on osteoblasts suggests another possibility. Namely, because osteoblasts contribute to the regulation of osteoclastogenesis, the reduced number of osteoblasts during G-CSF treatment may secondarily activate osteoclasts.…”

“…Long-term treatment with G-CSF is associated with development of clinically significant osteopenia, characterized by decreased BMD and vertebral compression fractures. (3,4) In a recent study, the incidence of osteopenia in patients with severe congenital neutropenia (SCN) treated chronically with G-CSF was 28%. (3) Similarly, long-term exposure to G-CSF in mice leads to a decrease in cortical and trabecular bone, suggesting that it is G-CSF and not the underlying disease that is causing osteopenia in patients with SCN.…”

“…(3) Similarly, long-term exposure to G-CSF in mice leads to a decrease in cortical and trabecular bone, suggesting that it is G-CSF and not the underlying disease that is causing osteopenia in patients with SCN. (4,5) There is evidence that G-CSF induces osteopenia in part by stimulating osteoclast activity. G-CSF treatment in-creases osteoclast number in treated mice and increases the level of urine deoxypyridinoline in humans.…”

Bone mineralization and turnover in children with congenital neutropenia, and its relationship to treatment with recombinant human granulocyte‐colony stimulating factor

“…Normal G-CSF-treated mononuclear cells have increased osteoclastogenic potential compared to untreated cells (Purton et al, 1996), and neutrophils stimulated by G-CSF produce cytokines (Roesler et al, 1991) which may stimulate bone resorption. Mice treated with G-CSF show a significant increase in osteoclast numbers (Lee et al, 1991), whereas transgenic mice overexpressing human G-CSF develop osteoporosis (Takahashi et al, 1996).…”