Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton
Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin, and its expression in...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/73539 |
| _version_ | 1797998541287718912 |
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| author | Bhaba K Das Lei Wang Toshifumi Fujiwara Jian Zhou Nukhet Aykin-Burns Kimberly J Krager Renny Lan Samuel G Mackintosh Ricky Edmondson Michael L Jennings Xiaofang Wang Jian Q Feng Tomasa Barrientos Jyoti Gogoi Aarthi Kannan Ling Gao Weirong Xing Subburaman Mohan Haibo Zhao |
| author_facet | Bhaba K Das Lei Wang Toshifumi Fujiwara Jian Zhou Nukhet Aykin-Burns Kimberly J Krager Renny Lan Samuel G Mackintosh Ricky Edmondson Michael L Jennings Xiaofang Wang Jian Q Feng Tomasa Barrientos Jyoti Gogoi Aarthi Kannan Ling Gao Weirong Xing Subburaman Mohan Haibo Zhao |
| author_sort | Bhaba K Das |
| collection | DOAJ |
| description | Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin, and its expression increases during osteoclast differentiation. Nonetheless, the precise functions of Tfr1 and Tfr1-mediated iron uptake in osteoclast biology and skeletal homeostasis remain incompletely understood. To investigate the role of Tfr1 in osteoclast lineage cells in vivo and in vitro, we crossed Tfrc (encoding Tfr1)-floxed mice with Lyz2 (LysM)-Cre and Cathepsin K (Ctsk)-Cre mice to generate Tfrc conditional knockout mice in myeloid osteoclast precursors (Tfr1ΔLysM) or differentiated osteoclasts (Tfr1ΔCtsk), respectively. Skeletal phenotyping by µCT and histology unveiled a significant increase in trabecular bone mass with normal osteoclast number in long bones of 10-week-old young and 6-month-old adult female but not male Tfr1ΔLysM mice. Although high trabecular bone volume in long bones was observed in both male and female Tfr1ΔCtsk mice, this phenotype was more pronounced in female knockout mice. Consistent with this gender-dependent phenomena, estrogen deficiency induced by ovariectomy decreased trabecular bone mass in Tfr1ΔLysM mice. Mechanistically, disruption of Tfr1 expression attenuated mitochondrial metabolism and cytoskeletal organization in mature osteoclasts in vitro by attenuating mitochondrial respiration and activation of the Src-Rac1-WAVE regulatory complex axis, respectively, leading to decreased bone resorption with little impact on osteoclast differentiation. These results indicate that Tfr1-mediated iron uptake is specifically required for osteoclast function and is indispensable for bone remodeling in a gender-dependent manner. |
| first_indexed | 2024-04-11T10:49:20Z |
| format | Article |
| id | doaj.art-e7aaa3c107a7445d8a2e1c1f94e4180c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:49:20Z |
| publishDate | 2022-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e7aaa3c107a7445d8a2e1c1f94e4180c2022-12-22T04:28:57ZengeLife Sciences Publications LtdeLife2050-084X2022-06-011110.7554/eLife.73539Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeletonBhaba K Das0https://orcid.org/0000-0003-0256-5489Lei Wang1Toshifumi Fujiwara2Jian Zhou3Nukhet Aykin-Burns4https://orcid.org/0000-0001-8574-4102Kimberly J Krager5Renny Lan6Samuel G Mackintosh7Ricky Edmondson8Michael L Jennings9Xiaofang Wang10Jian Q Feng11Tomasa Barrientos12Jyoti Gogoi13Aarthi Kannan14Ling Gao15Weirong Xing16Subburaman Mohan17https://orcid.org/0000-0003-0063-986XHaibo Zhao18https://orcid.org/0000-0003-0836-7555Southern California Institute for Research and Education, Long Beach, United StatesDepartment of Orthopedics, The Third People’s Hospital of Hefei, Third Clinical College, Anhui Medical University, Hefei, China; Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, United StatesCenter for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, United States; Department of Orthopedic Surgery, Kyushu University Hospital, Fukuoka, JapanDepartment of Orthopedics, First Affiliated Hospital, Anhui Medical University, Hefei, ChinaDivision of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, United StatesDivision of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, United StatesDepartment of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, United StatesDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, United StatesDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, United StatesDepartment of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, United StatesDepartment of Biomedical Sciences, Texas A&M University, Dallas, United StatesDepartment of Biomedical Sciences, Texas A&M University, Dallas, United StatesDepartment of Orthopedics, Duke University, Durham, United StatesSouthern California Institute for Research and Education, Long Beach, United StatesSouthern California Institute for Research and Education, Long Beach, United States; Division of Dermatology, Department of medicine, Long Beach VA Healthcare System, Long Beach, United StatesSouthern California Institute for Research and Education, Long Beach, United States; Division of Dermatology, Department of medicine, Long Beach VA Healthcare System, Long Beach, United StatesMusculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, United StatesMusculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, United StatesSouthern California Institute for Research and Education, Long Beach, United States; Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, United States; Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, United StatesIncreased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin, and its expression increases during osteoclast differentiation. Nonetheless, the precise functions of Tfr1 and Tfr1-mediated iron uptake in osteoclast biology and skeletal homeostasis remain incompletely understood. To investigate the role of Tfr1 in osteoclast lineage cells in vivo and in vitro, we crossed Tfrc (encoding Tfr1)-floxed mice with Lyz2 (LysM)-Cre and Cathepsin K (Ctsk)-Cre mice to generate Tfrc conditional knockout mice in myeloid osteoclast precursors (Tfr1ΔLysM) or differentiated osteoclasts (Tfr1ΔCtsk), respectively. Skeletal phenotyping by µCT and histology unveiled a significant increase in trabecular bone mass with normal osteoclast number in long bones of 10-week-old young and 6-month-old adult female but not male Tfr1ΔLysM mice. Although high trabecular bone volume in long bones was observed in both male and female Tfr1ΔCtsk mice, this phenotype was more pronounced in female knockout mice. Consistent with this gender-dependent phenomena, estrogen deficiency induced by ovariectomy decreased trabecular bone mass in Tfr1ΔLysM mice. Mechanistically, disruption of Tfr1 expression attenuated mitochondrial metabolism and cytoskeletal organization in mature osteoclasts in vitro by attenuating mitochondrial respiration and activation of the Src-Rac1-WAVE regulatory complex axis, respectively, leading to decreased bone resorption with little impact on osteoclast differentiation. These results indicate that Tfr1-mediated iron uptake is specifically required for osteoclast function and is indispensable for bone remodeling in a gender-dependent manner.https://elifesciences.org/articles/73539transferrintransferrin receptor 1osteoclastbone resorptionbone remodelingmitochondria |
| spellingShingle | Bhaba K Das Lei Wang Toshifumi Fujiwara Jian Zhou Nukhet Aykin-Burns Kimberly J Krager Renny Lan Samuel G Mackintosh Ricky Edmondson Michael L Jennings Xiaofang Wang Jian Q Feng Tomasa Barrientos Jyoti Gogoi Aarthi Kannan Ling Gao Weirong Xing Subburaman Mohan Haibo Zhao Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton eLife transferrin transferrin receptor 1 osteoclast bone resorption bone remodeling mitochondria |
| title | Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton |
| title_full | Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton |
| title_fullStr | Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton |
| title_full_unstemmed | Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton |
| title_short | Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton |
| title_sort | transferrin receptor 1 mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton |
| topic | transferrin transferrin receptor 1 osteoclast bone resorption bone remodeling mitochondria |
| url | https://elifesciences.org/articles/73539 |
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