YC-1 alleviates bone loss in ovariectomized rats by inhibiting bone resorption and inducing extrinsic apoptosis in osteoclasts
| Autor: | Shao-Jiun Chou, Mao-Hsiung Yen, Jia Fwu Shyu, Jin-Wen Wang, Kuo-Cheng Lu, Chin-Bin Yeh, Jui-Lin Chien, Tzu-Hui Chu, Tien Hua Chen, Wei Yu Chen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Indazoles Cell Survival Endocrinology Diabetes and Metabolism Ovariectomy Osteoporosis Osteoclasts Apoptosis Bone resorption Bone remodeling Nitric oxide Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Endocrinology Osteoclast Internal medicine medicine Animals Humans Orthopedics and Sports Medicine Bone Resorption Lumbar Vertebrae Osteoblasts Bone Density Conservation Agents business.industry Calpain General Medicine X-Ray Microtomography medicine.disease Actins 030104 developmental biology medicine.anatomical_structure src-Family Kinases chemistry Ovariectomized rat Female business cGMP-dependent protein kinase Signal Transduction |
| Zdroj: | Journal of bone and mineral metabolism. 36(5) |
| ISSN: | 1435-5604 |
| Popis: | Osteoporosis is a major health problem in postmenopausal women and the elderly that leads to fractures associated with substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, and the risk of fragility fractures has not yet been eliminated. There remains an unmet need for a broader range of therapeutics. Previous studies have shown that YC-1 has important regulatory functions in the cardiovascular and nervous systems. Many of the YC-1 effector molecules in platelets, smooth muscle cells and neurons, such as cGMP and μ-calpain, also have important functions in osteoclasts. In this study, we explored the effects of YC-1 on bone remodeling and determined the potential of YC-1 as a treatment for postmenopausal osteoporosis. Micro-computed tomography of lumbar vertebrae showed that YC-1 significantly improved trabecular bone microarchitecture in ovariectomized rats compared with sham-operated rats. YC-1 also significantly reversed the increases in serum bone resorption and formation in these rats, as measured by enzyme immunoassays for serum CTX-1 and P1NP, respectively. Actin ring and pit formation assays and TRAP staining analysis showed that YC-1 inhibited osteoclast activity and survival. YC-1 induced extrinsic apoptosis in osteoclasts by activating caspase-3 and caspase-8. In osteoclasts, YC-1 stimulated μ-calpain activity and inhibited Src activity. Our findings provide proof-of-concept for YC-1 as a novel antiresorptive treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone. |
| Databáze: | OpenAIRE |
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