Abstract
The nuclear receptor and transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), regulates the activity of other transcription factors in the adipogenic differentiation and inflammatory response pathways. We examined the possible function of the PPAR-gamma pathway in osteoclast (Ocl) formation from CD34(+) hematopoietic stem cells (CD34(+) HSCs), using a co-culture system comprised of human mesenchymal stem cells (hMSCs) and CD34(+) HSCs, both derived from bone marrow. Ocl formation in this co-culture system is enhanced by the addition of exogenous osteoprotegerin ligand (OPGL), an essential Ocl differentiation factor, and macrophage-colony stimulating factor (M-CSF). The data indicate that soluble OPGL (sOPGL) and M-CSF stimulate Ocl formation in the co-cultures up to 4-fold compared with CD34(+) HSCs alone treated with sOPGL and M-CSF. CD34(+) HSCs, but not hMSCs, express PPAR-gamma, and 15-deoxy-Delta(12, 14)-prostaglandin-J2 (15d-PG-J2), a PPAR-gamma agonist, completely blocked the effects of sOPGL and M-CSF on Ocl formation and activity. The inhibitory effect of 15d-PG-J2 is specific to the Ocl lineage in both human and mouse models of osteoclastogenesis. Accordingly, parallel experiments demonstrate that sOPGL activates the NF-kappaB pathway within mouse Ocl progenitors, and this effect was abolished by 15d-PG-J2. These data establish a link between PPAR-gamma and OPGL signaling within Ocl progenitors, and support a role for PPAR-gamma pathway in the modulation of osteoclastogenesis.
Highlights
Osteoclasts (Ocls)1 arise from precursor cells of the monocyte/macrophage lineage and are the primary cells responsible for physiological and pathological bone resorption
We examined the possible function of the PPAR-␥ pathway in osteoclast (Ocl) formation from CD34؉ hematopoietic stem cells (CD34؉ HSCs), using a co-culture system comprised of human mesenchymal stem cells and CD34؉ HSCs, both derived from bone marrow
Using RT-PCR we found that both OPG and osteoprotegerin ligand (OPGL) mRNA were expressed by human mesenchymal stem cells (hMSCs), and that osteogenic differentiation of hMSCs was associated with a decline in OPGL mRNA levels (Fig. 1A, top panel) and a concomitant increase in OPG mRNA levels
Summary
Osteoclasts (Ocls) arise from precursor cells of the monocyte/macrophage lineage and are the primary cells responsible for physiological and pathological bone resorption. PPAR-␥ cooperates with members of the CAAT/ enhancer-binding protein family to promote adipocyte differentiation in certain cell types [14], and it inhibits gene expression in monocytes/macrophages, in part by antagonizing the activity of other transcription factors, including NF-B and AP-1 [9]. The NF-B family of transcriptional activators regulates the expression of a variety of cytokines involved in Ocl differentiation, including IL-1, TNF-␣, IL-6, and granulocyte/macrophage-colony stimulating factor (GM-CSF) [15]. Consistent with these findings, mice with a deletion of the gene encoding p50/p52 heterodimer of the NF-B/Rel family exhibited osteopetrosis due to a deficiency in Ocl differentiation [16, 17]. We found that CD34ϩ HSCs, but not hMSCs, expressed PPAR-␥ and that activation of PPAR-␥ pathway in Ocl precursors inhibited sOPGL-induced NF-B activation, and blocked sOPGL-induced Ocl formation and activity
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