Transforming growth factor-β1 (TGF-β) stimulates the osteoclast-forming potential of peripheral blood hematopoietic precursors in a lymphocyte-rich microenvironment

Massey, Helen M.; Scopes, John; Horton, Michael A.; Flanagan, Adrienne M.

doi:10.1016/s8756-3282(01)00432-x

Cited by 55 publications

(45 citation statements)

References 27 publications

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“…Published studies of human osteoclast lineage cell responses to TGF-β have been restricted to differentiation responses. With respect to these responses, TGF-β has been reported to induce differentiation of precursors when cultured with RANKL and M-CSF, similar to murine osteoclast precursor responses [6,47].…”

Section: Discussionmentioning

confidence: 77%

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Gingery

Bradley

Pederson

et al. 2008

Experimental Cell Research

162

120

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To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX L expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

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Section: Discussionmentioning

confidence: 77%

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Gingery

Bradley

Pederson

et al. 2008

Experimental Cell Research

162

120

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“…It is already well documented that hypoxia increases VEGF production by osteoblasts (Steinbrech et al, 1999(Steinbrech et al, , 2000aAkeno et al, 2001), and VEGF production by human peripheral blood-derived macrophages is also strongly upregulated by hypoxia (Lewis et al, 1999). Similarly, IGF-1 and TGFb, produced by osteoblasts in response to low oxygen (Steinbrech et al, 2000b;Warren et al, 2001) are also stimulators of osteoclast formation (Hill et al, 1995;Fuller et al, 2000;Massey et al, 2001).…”

Section: Discussionmentioning

confidence: 97%

“…Therefore, atmospheric oxygen levels are likely to be inhibitory or perhaps even somewhat toxic for osteoclast marrow precursor cells. Osteoclasts can additionally form from mononuclear precursors present in circulating human blood (Massey et al, 2001), a process which is also stimulated dramatically by culture in 2% O 2 . Thus, it seems reasonable to suppose that when promonocytic cells extravasate from blood, where PO 2 levels are normally in the range 5-12%, into the interstitial microenvironments of bone, where PO 2 may be lower, osteoclast formation will be favored.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia is a major stimulator of osteoclast formation and bone resorption

Arnett

Gibbons

Utting

et al. 2003

Journal Cellular Physiology

266

204

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Hypoxia is known to act as a general stimulator of cells derived from marrow precursors. We investigated the effect of oxygen tension on the formation and function of osteoclasts, the cells responsible for bore resorption, which are of promonocytic origin. Using 7-and 13-day cultures of mouse marrow cells on ivory discs, we found that reducing oxygen tension from the ambient atmospheric level of 20% by increasing the proportion of nitrogen caused progressive increases in the formation of multinucleated osteoclasts and resorption pits. Peak effects occurred in 2% oxygen, where stimulations of resorption up to 21-fold were measured. Significant stimulations of osteoclast formation and resorption were observed even in severely hypoxic cultures gassed with 0.2% oxygen. Short-term cultures of cells disaggregated from rat bones indicated that hypoxia did not alter the resorptive activity of mature osteoclasts, but reduced their survival or adherence. In 3-day organ cultures of mouse calvarial bones, exposure to 2% oxygen resulted in maximal, fivefold stimulation of osteoclast-mediated calcium release, an effect equivalent to that of prostaglandin E 2 (PGE 2 ), a reference osteolytic agent. Hypoxia also caused a moderate acidosis in calvarial cultures, presumably as a result of increased anaerobic metabolism; this observation is significant because osteoclast activation is dependent on extracellular acidification. Our experiments reveal a previously-overlooked mechanism of considerable potential importance for the regulation of bone destruction. These findings may help explain the bone loss associated with a wide range of pathological states involving local or systemic hypoxia, and emphasize the importance of the vasculature in bone.

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“…To obtain BMMs, mouse bone marrow cells were collected from the tibiae and femora of the mice, and cultured for 3 days in ␣-MEM containing 10% FBS and M-CSF (50 ng/ml) in 100-mm-diameter type I collagen-coated culture dishes (IWAKI-Asahi Glass) (1 ϫ 10 7 cells/10 ml/dish). To promote the efficiency of osteoclast differentiation, human TGF-␤ (1 ng/ml) was added to the culture medium together with M-CSF, according to the previous reports (25)(26)(27)(37)(38)(39). After culturing for 3 days, floating cells were gently removed by rinsing with PBS, and cells remaining attached to the culture plates were collected by treatment with trypsin-EDTA (Invitrogen Life Technologies) and used as BMMs.…”

Section: Cell Culturesmentioning

confidence: 99%

Identification and Characterization of the Precursors Committed to Osteoclasts Induced by TNF-Related Activation-Induced Cytokine/Receptor Activator of NF-κB Ligand

Mochizuki

Miki

Kawawa

et al. 2006

The Journal of Immunology

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Osteoclasts are terminally differentiated from cells of monocyte/macrophage lineage by stimulation with TNF-related activation-induced cytokine (TRANCE) (receptor activator of NF-κB ligand/osteoprotegerin ligand/osteoclast differentiation factor/TNFSF11/CD254). In the present study, we attempted to determine when and how the cell fate of precursors becomes committed to osteoclasts following TRANCE stimulation. Although mouse bone marrow-derived macrophages (BMMs) were able to differentiate into either osteoclasts or dendritic cells, the cells no longer differentiated into dendritic cells after treatment with TRANCE for 24 h, indicating that their cell fate was committed to osteoclasts. Committed cells as well as BMMs were still quite weak in tartrate-resistant acid phosphatase activity, an osteoclast marker, and incorporated zymosan particles by phagocytosis. Interestingly, committed cells, but not BMMs, could still differentiate into osteoclasts even after incorporation of the zymosan particles. Furthermore, IL-4 and IFN-γ, potent inhibitors of osteoclast differentiation, failed to inhibit osteoclast differentiation from committed cells, and blocking of TRANCE stimulation by osteoprotegerin resulted in cell death. Adhesion to culture plates was believed to be essential for osteoclast differentiation; however, committed cells, but not BMMs, differentiated into multinucleated osteoclasts without adhesion to culture plates. Although LPS activated the NF-κB-mediated pathway in BMMs as well as in committed cells, the mRNA expression level of TNF-α in the committed cells was significantly lower than that in BMMs. These results suggest that characteristics of the committed cells induced by TRANCE are distinctively different from that of BMMs and osteoclasts.

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Transforming growth factor-β1 (TGF-β) stimulates the osteoclast-forming potential of peripheral blood hematopoietic precursors in a lymphocyte-rich microenvironment

Cited by 55 publications

References 27 publications

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Hypoxia is a major stimulator of osteoclast formation and bone resorption

Identification and Characterization of the Precursors Committed to Osteoclasts Induced by TNF-Related Activation-Induced Cytokine/Receptor Activator of NF-κB Ligand

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