Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
| Autor: | Yonghan He, Yuko Fujiwara, Li Han, Keisha M. Cawley, Daohong Zhou, Jinhu Xiong, Ha-Neui Kim, Ryan S. MacLeod, Charles A. O'Brien, Maria Almeida, Elisabeth Ferreira, Robert L. Jilka, Srividhya Iyer, Jeff D. Thostenson |
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| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Senescence Aging medicine.medical_specialty Bone disease medicine.medical_treatment Biology Osteocytes Mice 03 medical and health sciences 0302 clinical medicine Osteoclast Internal medicine Conditional gene knockout Cortical Bone medicine Animals Bone Resorption Cellular Senescence Mice Knockout RANK Ligand General Medicine medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Endocrinology Cytokine RANKL 030220 oncology & carcinogenesis Osteocyte biology.protein Medicine Female Bone Biology Cortical bone Research Article |
| Zdroj: | JCI Insight JCI Insight, Vol 5, Iss 19 (2020) |
| ISSN: | 2379-3708 |
| Popis: | In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone. Induction of senescence in osteoblast-like cells stimulates RANKL production, providing a possible explanation for the increased cortical bone resorption that occurs with age. |
| Databáze: | OpenAIRE |
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