GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease
Abstract Background Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the G...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-024-03132-x |
| _version_ | 1797219570357895168 |
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| author | Chung-Hsing Wang Yu‐Nan Huang Wen-Ling Liao Ai-Ru Hsieh Wei-De Lin Kai-Wen Liu Wen-Li Lu Chieh‐Chen Huang Yin-Hsiu Chien Ni-Chung Lee Pen-Hua Su Fuu-Jen Tsai |
| author_facet | Chung-Hsing Wang Yu‐Nan Huang Wen-Ling Liao Ai-Ru Hsieh Wei-De Lin Kai-Wen Liu Wen-Li Lu Chieh‐Chen Huang Yin-Hsiu Chien Ni-Chung Lee Pen-Hua Su Fuu-Jen Tsai |
| author_sort | Chung-Hsing Wang |
| collection | DOAJ |
| description | Abstract Background Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. Methods We selected 8115 patients with osteoporosis (T-score ≤ − 2.5) and 55,942 healthy individuals (T-score > − 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient’s cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. Results The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. Conclusions Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis. |
| first_indexed | 2024-04-24T12:35:45Z |
| format | Article |
| id | doaj.art-0c1baf8b9b3b4b928fe4f713814a049b |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-04-24T12:35:45Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-0c1baf8b9b3b4b928fe4f713814a049b2024-04-07T11:30:34ZengBMCOrphanet Journal of Rare Diseases1750-11722024-04-0119111610.1186/s13023-024-03132-xGBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher diseaseChung-Hsing Wang0Yu‐Nan Huang1Wen-Ling Liao2Ai-Ru Hsieh3Wei-De Lin4Kai-Wen Liu5Wen-Li Lu6Chieh‐Chen Huang7Yin-Hsiu Chien8Ni-Chung Lee9Pen-Hua Su10Fuu-Jen Tsai11Division of Genetics and Metabolism, Children’s Hospital of China Medical UniversityDepartment of Pediatrics, Chung Shan Medical University HospitalGraduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical UniversityDepartment of Statistics, Tamkang UniversitySchool of Post Baccalaureate Chinese Medicine, China Medical UniversityDivision of Genetics and Metabolism, Children’s Hospital of China Medical UniversityDivision of Genetics and Metabolism, Children’s Hospital of China Medical UniversityDepartment of Life Sciences, National Chung-Hsing UniversityDepartment of Pediatrics, National Taiwan University HospitalDepartment of Pediatrics, National Taiwan University HospitalDepartment of Pediatrics, Chung Shan Medical University HospitalDivision of Genetics and Metabolism, Children’s Hospital of China Medical UniversityAbstract Background Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. Methods We selected 8115 patients with osteoporosis (T-score ≤ − 2.5) and 55,942 healthy individuals (T-score > − 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient’s cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. Results The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. Conclusions Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.https://doi.org/10.1186/s13023-024-03132-xGaucher diseaseGBA1OsteoclastogenesisInflammasomeEndoplasmic reticulum stressOsteoporosis |
| spellingShingle | Chung-Hsing Wang Yu‐Nan Huang Wen-Ling Liao Ai-Ru Hsieh Wei-De Lin Kai-Wen Liu Wen-Li Lu Chieh‐Chen Huang Yin-Hsiu Chien Ni-Chung Lee Pen-Hua Su Fuu-Jen Tsai GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease Orphanet Journal of Rare Diseases Gaucher disease GBA1 Osteoclastogenesis Inflammasome Endoplasmic reticulum stress Osteoporosis |
| title | GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease |
| title_full | GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease |
| title_fullStr | GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease |
| title_full_unstemmed | GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease |
| title_short | GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease |
| title_sort | gba1 as a risk gene for osteoporosis in the specific populations and its role in the development of gaucher disease |
| topic | Gaucher disease GBA1 Osteoclastogenesis Inflammasome Endoplasmic reticulum stress Osteoporosis |
| url | https://doi.org/10.1186/s13023-024-03132-x |
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