Abstract
Aging is associated with cellular senescence followed by bone loss leading to bone fragility in humans. However, the regulators associated with cellular senescence in aged bones need to be identified. Hypoxia-inducible factor (HIF)−2α regulates bone remodeling via the differentiation of osteoblasts and osteoclasts. Here, we report that HIF-2α expression was highly upregulated in aged bones. HIF-2α depletion in male mice reversed age-induced bone loss, as evidenced by an increase in the number of osteoblasts and a decrease in the number of osteoclasts. In an in vitro model of doxorubicin-mediated senescence, the expression of Hif-2α and p21, a senescence marker gene, was enhanced, and osteoblastic differentiation of primary mouse calvarial preosteoblast cells was inhibited. Inhibition of senescence-induced upregulation of HIF-2α expression during matrix maturation, but not during the proliferation stage of osteoblast differentiation, reversed the age-related decrease in Runx2 and Ocn expression. However, HIF-2α knockdown did not affect p21 expression or senescence progression, indicating that HIF-2α expression upregulation in senescent osteoblasts may be a result of aging rather than a cause of cellular senescence. Osteoclasts are known to induce a senescent phenotype during in vitro osteoclastogenesis. Consistent with increased HIF-2α expression, the expression of p16 and p21 was upregulated during osteoclastogenesis of bone marrow macrophages. ChIP following overexpression or knockdown of HIF-2α using adenovirus revealed that p16 and p21 are direct targets of HIF-2α in osteoclasts. Osteoblast-specific (Hif-2αfl/fl;Col1a1-Cre) or osteoclast-specific (Hif-2αfl/fl;Ctsk-Cre) conditional knockout of HIF-2α in male mice reversed age-related bone loss. Collectively, our results suggest that HIF-2α acts as a senescence-related intrinsic factor in age-related dysfunction of bone homeostasis.
Highlights
Bone homeostasis is maintained by tight regulation of the interplay between two specific cell types: boneforming osteoblasts and bone-resorbing osteoclasts[1]
Because bone tissue is a complex system that consists of diverse cell types, including osteoblasts, osteocytes and osteoclasts along with various supporting cells, including hematopoietic cells, the upregulated Hif-2α expression shown in Fig. 1a, b might be associated with various cell types
This study showed that senescenceinduced Hypoxia-inducible factor (HIF)-2α expression upregulation in both osteoblasts and osteoclasts acts as a novel intrinsic mediator of age-related bone loss
Summary
Bone homeostasis is maintained by tight regulation of the interplay between two specific cell types: boneforming osteoblasts and bone-resorbing osteoclasts[1]. Imbalances in bone homeostasis cause severe bone diseases, including osteoporosis, the most prevalent chronic disease in aging adults. Osteoblast differentiation is governed by osteoblast-specific transcription factors, including runt-related transcription factor-2 (RUNX2)[6] and osterix[7]. Mature osteoblasts are responsible for the assembly of matrix proteins, including collagen type I (COL1A1), bone integrin-binding sialoprotein (IBSP), osteopontin (OPN) and osteocalcin (OCN)[8], and are characterized by an increase in alkaline phosphatase (ALP) activity[9]. Age-related bone loss was shown to be caused by a deficit in bone formation[10]. Osteoblast dysfunction is the main cause of age-related bone loss in humans and results from two distinct types of mechanisms. Extrinsic mechanisms are mediated by changes in the bone microenvironment associated with hormones and growth factors, whereas intrinsic mechanisms are mediated by osteoblast senescence following reductions in the number, lifespan, and differentiation of osteoblasts[11]
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