Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO

Abstract

Myelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor ␤1 (TGF-␤1) in the pathogenesis of myelofibrosis has been documented, but the mechanisms mediating osteosclerosis remain unclear. Here, we used mice deficient in osteoprotegerin (OPG), a secreted inhibitor of bone resorption, to determine whether osteosclerosis occurs through a deregulation of osteoclastogenesis. Marrow cells from opg-deficient mice (opg ؊/؊ ) or wild-type (WT) littermates were infected with a retrovirus encoding TPO and engrafted into an opg ؊/؊ or WT background for long-term reconstitution. The 4 combinations of graft/host (WT/WT, opg ؊/؊ /opg ؊/؊ , opg ؊/؊ /WT, and WT/opg ؊/؊ ) were studied. Elevation of TPO and TGF-␤1 levels in plasma was similar in the 4 experimental groups and all the mice developed a similar myeloproliferative syndrome associated with severe myelofibrosis. Osteosclerosis developed in WT hosts engrafted with WT or opg ؊/؊ hematopoietic cells and was associated with increased OPG levels in plasma and decreased osteoclastogenesis. In contrast, opg ؊/؊ hosts exhibited an osteoporotic phenotype and a growth of bone trabeculae was rarely seen. These findings suggest that osteosclerosis in mice with TPO IntroductionBone remodeling depends on the tightly integrated activity of 2 distinct cell types, the osteoblasts, which construct bone, and the osteoclasts, which resorb bone (for reviews, see Ducy et al 1 and Teitelbaum 2 ). Studies of spontaneous mutations and the development of genetically manipulated mice have improved the understanding of the complex processes involved in bone remodeling. Formation of bone is dependent on the number, maturation, and functions of the osteoblasts. Osteoblasts derive from mesenchymal progenitors through the regulatory action of cell-cell and cellmatrix interactions 3 and by the actions of growth factors produced locally or present in the circulation. 4 Among these growth factors, the most important are insulin-like growth factor I (IGF-I), which increases the differentiation of osteoblasts, 5 members of the fibroblast growth factor (FGF) family, which indirectly stimulate their proliferation, 6 and members of the transforming growth factor ␤ (TGF-␤) multigene family (for a review, see Centrella et al 7 ). Bone morphogenetic proteins (BMPs) have the ability to induce osteoblast differentiation, whereas the actions of TGF-␤ may be stimulatory or inhibitory. [7][8][9][10] On the other hand, bone resorption is controlled by monocyte-derived multinucleated, giant osteoclasts. 2 Extensive, recent studies have demonstrated that the differentiation of osteoclasts requires 3 main factors. Macrophage colonystimulating factor/colony-stimulating factor 1 (M-CSF/CSF-1) controls the survival and proliferation of monocytic progenitors. 11,12 RANKL (also known as OPGL/ODF/TRANCE) binds to the RANK receptor (receptor activator of nuclear factor B) expressed on the membrane of osteoclast progenitor cells 1...

Interleukin‐11 as an osteoprotegerin‐inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis

“…Although the over-expression of TPO in bone marrow cells of mice was known to result in OS as well as myelofibrosis [7], it was reported that OS had not occurred by the over-expression of TPO in OPG-deficient mice [13]. This conclusion was based not on clinical examination but an in vivo study; however, it may suggest an unspecific role of OPG in the development of OS.…”

“…Focusing on primary myelofibrosis, which frequently causes OS at the terminal stage, OPG was also suspected as an etiological factor of OS [13]. Although the over-expression of TPO in bone marrow cells of mice was known to result in OS as well as myelofibrosis [7], it was reported that OS had not occurred by the over-expression of TPO in OPG-deficient mice [13].…”

Circasemidian rather than circadian variation of circulating osteoprotegerin in clinical health

“…In particular, hormones such as PTH [10] and glucocorticoids [11,12] have been reported to decrease OPG concentrations while anabolic agents such as estrogens, transforming growth factor β, related bone morphogenic factor and thrombopoietin [13][14][15][16] have been shown to enhance the OPG production in the osteoblastic and bone stromal cells. Recent studies [17][18][19] have described a bimodal pattern for the variation along the 24-h scale of circulating PTH, with a major peak during the night and a secondary peak in the late afternoon.…”

Myelofibrosis with Myeloid Metaplasia: New Developments in Pathogenesis and Treatment

“…Osteoprotegerin is an important inhibitor of oseoclastogenesis and animals engineered to overexpress OPG develop osteopetrosis (28). Thrombopoietin up-regulates OPG expression in animal models and therefore can explain the osteosclerosis seen in this disease (29). MMM is associated with significant new vessel formation (13).…”