Abstract
Functional cross-talk between osteoblasts and osteoclasts is a key process for bone homeostasis. Although osteoblast hypoxia-inducible factor-1α (HIF-1α) pathway activation results in impaired osteoclastogenesis via the direct regulation of osteoprotegerin (OPG), it is unclear whether there are other efficient mediators are involved in osteoblast HIF-1α pathway activation-restrained osteoclast formation. In addition to upregulated OPG, we observed that osteoblast HIF-1α activation led to increased interleukin-33 (IL-33) expression, which was found to inhibit osteoclastogenesis. Mechanistically, HIF-1α facilitates IL-33 expression by binding to −1,504/−1,500 bp on the Il-33 promoter. IL-33, thereby, acts on bone marrow-derived monocytes (BMMs) to reduce their osteoclastic differentiation. Moreover, microRNA-34a-5p (miR-34a-5p)-inhibited Notch1 activation was observed to play a central role in this process. Thereby, the identification of IL-33-miR-34a-5p-Notch1 pathway in the inhibitory effect of osteoblast HIF-1α pathway on osteoclastogenesis uncovers a new mechanism for understanding the effects of HIF-1α on bone remodeling.
Highlights
As a dynamic tissue, bone undergoes life-long remodeling: osteoblasts regulated bone formation and osteoclasts mediated bone destruction or resorption [1]
Before the collection of culture medium of osteoblasts infected with adenovirus expressing green fluoresence protein (Ad-GFP) (CM-GFP) or culture medium of osteoblasts infected with adenovirus expressing Cre recombinase (Ad-CRE) (CM-CRE), the cells were changed to incubate with α-MEM without serum or penicillin/streptomycin
tartrateresistant acid phosphatase (TRAP) staining and TRAP activity assays results revealed that compared with group stimulated with the conditioned culture medium of osteoblasts infected with Ad-GFP (CM-GFP), the conditioned culture medium of osteoblasts infected with Ad-CRE (CM-CRE) treatment strongly reduced osteoclastogenesis (Figures 1B–D)
Summary
Bone undergoes life-long remodeling: osteoblasts regulated bone formation and osteoclasts mediated bone destruction or resorption [1]. The functional cross-talk between osteoblasts and osteoclasts is a key process for bone homeostasis. Both defects in the cells and obstruction. When under the effects of certain physical and chemical factors, osteoblasts can express some cytokines to regulate osteoclast formation [5, 6]. Studies have revealed that differentiated osteoblasts can express interleukin-33 (IL-33) to block osteoclast formation from bone marrow-derived macrophages [7, 8], and that rates of osteoclastogenesis are higher in IL-33 receptor-ST2 deficient mice [8]. Whether IL-33 is involved in the cross-talk between osteoblasts hypoxia-inducible factor (HIF)-1α pathway activation and osteoclasts formation is unknown
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