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Osteoblasts/Osteocytes sirtuin6 Is Vital to Preventing Ischemic Osteonecrosis Through Targeting VDR-RANKL Signaling
Zhongkai Zhang1, Yiping Song1, Sung Il Wang1
1Department of Orthopaedic Surgery, Chonbuk National University Medical School, Jeonju, Republic of Korea.
Abstract:
Ischemic osteonecrosis (ION) can produce permanent deformity and osteoarthritis in the femoral head and other joints. No biologic treatment has been established, and the molecular mechanisms involved in the pathogenesis of ION have not been elucidated. In this work, we found that treatment with sirtuin6 (Sirt6) suppressed inflammatory cytokines, bone resorption, progression of osteoarthritis, and reduced bone deformity in an ION mouse model. We used a deacetylase mutant adenovirus to confirm that those effects were caused by the deacetylase function of Sirt6. Among the osteoclastogenic factors of osteoblasts, only the receptor activator of NF-κb ligand (RANKL) level changed in response to Sirt6 knockout in primary osteoblasts. In particular, the vitamin D receptor physically interacted with Sirt6 and induced recruitment of Sirt6 around RANKL promoters. Finally, Tg mice overexpressing Sirt6 resisted osteocyte death, bone resorption, and progression of osteoarthritis after ischemic surgery, whereas osteoblast/osteocyte-specific Sirt6 knockout mice showed aggravated bone loss and severe deformity. Our findings demonstrate that administration of Sirt6 prevents bone loss and osteoarthritis in ischemic conditions. Activation of Sirt6 in osteoblasts/osteocytes could be a new therapeutic approach to treating ION of the femoral head and other bone regions. © 2020 American Society for Bone and Mineral Research (ASBMR).
Insights
Sirtuin6 (Sirt6) protein administration effectively treats ischemic osteonecrosis (ION) by reducing inflammation, bone resorption, and deformity. Activating Sirt6 in bone cells offers a promising new therapy for ION and osteoarthritis.
Area of Science:
- Bone Biology
- Molecular Mechanisms of Disease
- Osteoarthritis Pathogenesis
Background:
- Ischemic osteonecrosis (ION) causes joint deformity and osteoarthritis, with no established biologic treatments.
- The molecular pathways driving ION pathogenesis remain poorly understood.
- Current therapeutic strategies for ION are limited.
Purpose of the Study:
- To investigate the role of sirtuin6 (Sirt6) in the pathogenesis of ischemic osteonecrosis (ION).
- To determine if Sirt6 can serve as a therapeutic target for preventing bone loss and deformity in ION.
- To elucidate the molecular mechanisms by which Sirt6 influences bone metabolism in ION.
Main Methods:
- Utilized an ION mouse model to assess the effects of Sirt6 treatment.
- Employed a deacetylase mutant adenovirus to confirm Sirt6's functional mechanism.
- Performed Sirt6 knockout in primary osteoblasts and generated transgenic (Tg) and knockout mice for in vivo validation.
- Investigated the interaction between Sirt6, vitamin D receptor, and RANKL promoter.
Main Results:
- Sirt6 administration suppressed inflammatory cytokines, bone resorption, osteoarthritis progression, and bone deformity in an ION mouse model.
- Sirt6's deacetylase function was confirmed to mediate these protective effects.
- Sirt6 modulated the receptor activator of NF-κb ligand (RANKL) in osteoblasts and interacted with the vitamin D receptor to regulate RANKL promoters.
- Overexpression of Sirt6 conferred resistance to ischemic injury, while Sirt6 deficiency exacerbated bone loss and deformity.
Conclusions:
- Sirt6 administration is a potent therapeutic strategy for preventing bone loss and osteoarthritis in ischemic conditions.
- Targeting Sirt6 activation in osteoblasts and osteocytes presents a novel therapeutic approach for treating ION.
- Sirt6 plays a critical protective role in maintaining bone integrity following ischemic events.
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