Marrow Stromal Cells and Osteoclast Precursors Differentially Contribute to TNF-α-Induced Osteoclastogenesis In Vivo

Abstract

The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-κB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-α-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-α. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-α treatment or whether the recipient animals possess TNF-α-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-α requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-α increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-α is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-α depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-α may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.

Effect of Macrophage Colony-Stimulating Factor Receptor c-Fms Antibody on Lipopolysaccharide-Induced Pathological Osteoclastogenesis and Bone Resorption

“…Several previous studies have indicated that LPS induces the expression of inflammatory cytokines, such as TNF-a, IL-1, and IL-6, in vitro and in vivo. Furthermore, it has been reported that TNF-α induces M-CSF expression in stromal cells in vivo [42,44]. In our study, we found that LPS induced M-CSF expression in vivo.…”

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

“…Bone marrow stromal cells are indeed responsible for most of the effects of TNF-α and IL-1β on bone resorption through RANKL secretion [8]; and osteoblasts are responsible for bone formation. Figure 4 indicates that, while stromal cells and osteoblasts do not constitutively express ST2L mRNA, expression o this transcript is induced by TNF-α and IL-1β (Fig.…”

“…Moreover, bone resorption due to estrogen deficiency in women can be blocked by etanercept and anakinra, which are inhibitors of TNF-α or IL-1β respectively [6]. The mechanisms used by TNF-α and IL-1β to promote bone loss include activation of osteoclastogenesis, which occurs both directly [7,8] and through the induction of receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony stimulating factor (M-CSF) expression by stromal cells [8,9]. It is also generally recognized that both cytokines contribute to decrease bone mineral density by decreasing bone formation.…”

Pathological role of osteoclast costimulation in arthritis-induced bone loss

“…4A). Although the mechanisms underlying the enhanced osteoclastogenesis in hTNFtg mice may include the induction of RANKL in mesenchymal cells (11,14,27) or the increase in the number of osteoclast precursor cells in vivo (21,28), this result suggests a novel mechanism (i.e., the enhancement of the osteoclastogenic potential in the hTNFtg BMMs). Flow-cytometric analysis indicated that freshly isolated hTNFtg BMMs expressed a higher level of PIRs than WT BMMs, supporting the notion that the osteoclastogenic potential in the hTNFtg BMMs is enhanced (Fig.…”

“…Interestingly, the anti-TNF-␣ antibody has been shown to suppress bone damage in patients who had no clinical improvement in terms of pain and inflammation (19), suggesting that, under arthritic condition, TNF-␣ exerts an important direct action on bone, which is independent of its action on the immune system. Although there has been no in vivo evidence that TNF-␣ induces osteoclastogenesis in mice lacking RANKL signaling or that TNF-␣ rescues osteopetrosis in such mice (20)(21)(22), TNF-␣ clearly acts on osteoclast precursor cells and changes the responsiveness of the cells under certain conditions (13)(14)(15). However, the molecular mechanism underlying the enhanced osteoclastogenic potential of osteoclast precursor cells in the presence of TNF-␣ remains to be elucidated.…”