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2. FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

Author

Alvarez‐Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Miyata, Kohei, Mokuda, Sho, Sakai, Daisuke, Masuda, Koichi, Asahara, Hiroshi, and Lotz, Martin K

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Aging, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Musculoskeletal, Animals, Cells, Cultured, Forkhead Box Protein O1, Forkhead Box Protein O3, Homeostasis, Humans, Intervertebral Disc, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, aging, autophagy, FOXO, intervertebral disk, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Intervertebral disk (IVD) degeneration is a prevalent age-associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age-related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO-deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

Published
2018

4. Age‐related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc degeneration

Author

Alvarez‐Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Masuda, Koichi, and Lotz, Martin K

Subjects
Engineering, Health Sciences, Sports Science and Exercise, Biomedical Engineering, Pain Research, Chronic Pain, Aging, Prevention, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Aged, Animals, Forkhead Box Protein O1, Forkhead Box Protein O3, Humans, Intervertebral Disc, Intervertebral Disc Degeneration, Male, Mice, Inbred C57BL, Middle Aged, Biomedical and Clinical Sciences, Ophthalmology and Optometry, intervertebral disc, aging, FOXO, Clinical Sciences, Human Movement and Sports Sciences, Orthopedics, Biomedical engineering, Sports science and exercise
Abstract

Aging is a main risk factor for intervertebral disc (IVD) degeneration, the main cause of low back pain. FOXO transcription factors are important regulators of tissue homeostasis and longevity. Here, we determined the expression pattern of FOXO in healthy and degenerated human IVD and the associations with IVD degeneration during mouse aging. FOXO expression was assessed by immunohistochemistry in normal and degenerated human IVD samples and in cervical and lumbar IVD from 6-, 12-, 24-, and 36-month-old C57BL/6J mice. Mouse spines were graded for key histological features of disc degeneration in all the time points and expression of two key FOXO downstream targets, sestrin 3 (SESN3) and superoxide dismutase (SOD2), was assessed by immunohistochemistry. Histological analysis revealed that FOXO proteins are expressed in all compartments of human and mouse IVD. Expression of FOXO1 and FOXO3, but not FOXO4, was significantly deceased in human degenerated discs. In mice, degenerative changes in the lumbar spine were seen at 24 and 36 months of age whereas cervical IVD showed increased histopathological scores at 36 months. FOXO expression was significantly reduced in lumbar IVD at 12-, 24-, and 36-month-old mice and in cervical IVD at 36-month-old mice when compared with the 6-month-old group. The reduction of FOXO expression in lumbar IVD was concomitant with a decrease in the expression of SESN3 and SOD2. These findings suggest that reduced FOXO expression occurs in lumbar IVD during aging and precedes the major histopathological changes associated with lumbar IVD degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2682-2691, 2017.

Published
2017

29. Compensatory motion scaling for time-delayed robotic surgery

Author

Orosco, Ryan K., primary, Lurie, Benjamin, additional, Matsuzaki, Tokio, additional, Funk, Emily K., additional, Divi, Vasu, additional, Holsinger, F. Christopher, additional, Hong, Steven, additional, Richter, Florian, additional, Das, Nikhil, additional, and Yip, Michael, additional

Published
2020
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33. FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration.

Author

Alvarez-Garcia, Oscar, Alvarez-Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Miyata, Kohei, Mokuda, Sho, Sakai, Daisuke, Masuda, Koichi, Asahara, Hiroshi, Lotz, Martin K, Alvarez-Garcia, Oscar, Alvarez-Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Miyata, Kohei, Mokuda, Sho, Sakai, Daisuke, Masuda, Koichi, Asahara, Hiroshi, and Lotz, Martin K

Abstract

Intervertebral disk (IVD) degeneration is a prevalent age-associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age-related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO-deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

Published
2018

34. REDD1 deficiency impairs autophagy and mitochondrial biogenesis in articular cartilage and increases the severity of experimental osteoarthritis

Author

Alvarez-Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Plate, Lars, Kelly, Jeffery W., and Lotz, Martin K.

Subjects
Cartilage, Articular, Mice, Knockout, Organelle Biogenesis, Synovial Membrane, High Mobility Group Proteins, Apoptosis, AMP-Activated Protein Kinases, Osteoarthritis, Knee, Arthritis, Experimental, Immunohistochemistry, Menisci, Tibial, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Article, Autophagy-Related Protein 5, Mitochondria, DNA-Binding Proteins, Disease Models, Animal, Mice, Oxidative Stress, Chondrocytes, Autophagy, Animals, Humans, Microtubule-Associated Proteins, Transcription Factors
Abstract

Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.OA severity was histologically assessed in 4-month-old wild-type and REDD1REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury-induced OA.

Published
2017

35. Age-related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc degeneration.

Author

Alvarez-Garcia, Oscar, Alvarez-Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Masuda, Koichi, Lotz, Martin K, Alvarez-Garcia, Oscar, Alvarez-Garcia, Oscar, Matsuzaki, Tokio, Olmer, Merissa, Masuda, Koichi, and Lotz, Martin K

Abstract

Aging is a main risk factor for intervertebral disc (IVD) degeneration, the main cause of low back pain. FOXO transcription factors are important regulators of tissue homeostasis and longevity. Here, we determined the expression pattern of FOXO in healthy and degenerated human IVD and the associations with IVD degeneration during mouse aging. FOXO expression was assessed by immunohistochemistry in normal and degenerated human IVD samples and in cervical and lumbar IVD from 6-, 12-, 24-, and 36-month-old C57BL/6J mice. Mouse spines were graded for key histological features of disc degeneration in all the time points and expression of two key FOXO downstream targets, sestrin 3 (SESN3) and superoxide dismutase (SOD2), was assessed by immunohistochemistry. Histological analysis revealed that FOXO proteins are expressed in all compartments of human and mouse IVD. Expression of FOXO1 and FOXO3, but not FOXO4, was significantly deceased in human degenerated discs. In mice, degenerative changes in the lumbar spine were seen at 24 and 36 months of age whereas cervical IVD showed increased histopathological scores at 36 months. FOXO expression was significantly reduced in lumbar IVD at 12-, 24-, and 36-month-old mice and in cervical IVD at 36-month-old mice when compared with the 6-month-old group. The reduction of FOXO expression in lumbar IVD was concomitant with a decrease in the expression of SESN3 and SOD2. These findings suggest that reduced FOXO expression occurs in lumbar IVD during aging and precedes the major histopathological changes associated with lumbar IVD degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2682-2691, 2017.

Published
2017

39. Local Administration of Simvastatin Stimulates Healing of an Avascular Meniscus in a Rabbit Model of a Meniscal Defect

Author

Zhang, Shurong, primary, Matsushita, Takehiko, additional, Kuroda, Ryosuke, additional, Nishida, Kyohei, additional, Matsuzaki, Tokio, additional, Matsumoto, Tomoyuki, additional, Takayama, Koji, additional, Nagai, Kanto, additional, Oka, Shinya, additional, Tabata, Yasuhiko, additional, Nagamune, Kouki, additional, and Kurosaka, Masahiro, additional

Published
2016
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44. Fibular axes are not a reliable landmark for tibial mechanical axes of osteoarthritic knees that underwent total knee arthroplasty

Author

Kuroda, Yuichi, primary, Ishida, Kazunari, additional, Matsumoto, Tomoyuki, additional, Sasaki, Hiroshi, additional, Matsuzaki, Tokio, additional, Oka, Shinya, additional, Takayama, Koji, additional, Tei, Katsumasa, additional, Matsushita, Takehiko, additional, Tsumura, Nobuhiro, additional, Kuroda, Ryosuke, additional, and Kurosaka, Masahiro, additional

Published
2014
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48. Tibial internal rotation is affected by lateral laxity in cruciate-retaining total knee arthroplasty: an intraoperative kinematic study using a navigation system and offset-type tensor

Author

Matsuzaki, Tokio, primary, Matsumoto, Tomoyuki, additional, Kubo, Seiji, additional, Muratsu, Hirotsugu, additional, Matsushita, Takehiko, additional, Kawakami, Yohei, additional, Ishida, Kazunari, additional, Oka, Shinya, additional, Kuroda, Ryosuke, additional, and Kurosaka, Masahiro, additional

Published
2013
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50. Local Administration of Low-Dose Simvastatin-Conjugated Gelatin Hydrogel for Tendon–Bone Healing in Anterior Cruciate Ligament Reconstruction

Author

Oka, Shinya, primary, Matsumoto, Tomoyuki, additional, Kubo, Seiji, additional, Matsushita, Takehiko, additional, Sasaki, Hiroshi, additional, Nishizawa, Yuichiro, additional, Matsuzaki, Tokio, additional, Saito, Takashi, additional, Nishida, Kotaro, additional, Tabata, Yasuhiko, additional, Kurosaka, Masahiro, additional, and Kuroda, Ryosuke, additional

Published
2013
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