Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging
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Osteocyte survival is key to bone homeostasis and is perturbed in menopause and aging. However, it remains unknown how osteocyte-mediated maintenance of the skeleton is regulated by the osteoprotective factor semaphorin 3A (Sema3A), a secreted protein that is known to reduce bone resorption and enhance bone formation. Here, we show that estrogen induces osteocyte expression of Sema3A, which acts on its receptor on osteocytes to promote their survival and maintain bone homeostasis. Postnatal global and conditional deletion of Sema3a in osteoblastic cells resulted in a severe osteoporotic phenotype marked by fewer osteocytes. This phenotype was recapitulated by osteocyte-specific deficiency of either Sema3A or its receptor component neuropilin-1 (Nrp1). A stimulator of soluble guanylate cyclase-cGMP signaling mimicked Sema3A action and ameliorated bone loss after ovariectomy. We further show that serum levels of SEMA3A decreased with age or after menopause in humans. Thus, we provide a mechanistic insight into the estrogen action and a promising therapeutic approach to protect against bone-related aging.
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Autocrine loop impairment caused by estrogen deficiency induces an osteoporosis phenotype.
“Autocrine loop impairment caused by estrogen deficiency induces an osteoporosis phenotype.94”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [94]
Cites
Osteoporosis: now and the future
Rachner, T. D., Khosla, S., & Hofbauer, L. C. (2011) · The Lancet · doi:10.1016/s0140-6736(10)62349-5 · Cited by 2,696 · see citing works
Evidence for osteocyte regulation of bone homeostasis through RANKL expression
Nakashima, T., Hayashi, M., Fukunaga, T., Kurata, K., Oh-hora, M., Feng, J. Q., Bonewald, L. F., Kodama, T., Wutz, A., Wagner, E. F., et al. (2011) · Nature Medicine · doi:10.1038/nm.2452 · Cited by 1,778 · see citing works
Self-citationHayashi, S., & McMahon, A. P. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0597 · Cited by 1,347 · see citing works
Riociguat for the treatment of pulmonary arterial hypertension
Ghofrani, H.-A., Galiè, N., Grimminger, F., Grünig, E., Humbert, M., Jing, Z.-C., Keogh, A. M., Langleben, D., Kilama, M. O., Fritsch, A., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1209655 · Cited by 1,346 · see citing works
Matrix-embedded cells control osteoclast formation
Xiong, J., Onal, M., Jilka, R. L., Weinstein, R. S., Manolagas, S. C., & O'Brien, C. A. (2011) · Nature Medicine · doi:10.1038/nm.2448 · Cited by 1,304 · see citing works
Manolagas, S. C. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0024 · Cited by 1,210 · see citing works
Targeting cellular senescence prevents age-related bone loss in mice
Farr, J. N., Xu, M., Weivoda, M. M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4385 · Cited by 1,182 · see citing works
The Osteocyte: An Endocrine Cell … and More
Dallas, S. L., Prideaux, M., & Bonewald, L. F. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1026 · Cited by 1,042 · see citing works
Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer
Logan, M., Martin, J. F., Nagy, A., Lobe, C., Olson, E., & Tabin, C. (2002) · Genesis · doi:10.1002/gene.10092 · Cited by 1,022 · see citing works
Rodda, S. J., & McMahon, A. P. (2006) · Development · doi:10.1242/dev.02480 · Cited by 1,011 · see citing works
Estrogens and androgens in skeletal physiology and pathophysiology
Almeida, M., Laurent, M. R., Dubois, V., Claessens, F., O'Brien, C. A., Bouillon, R., Vanderschueren, D., & Manolagas, S. C. (2017) · Physiological Reviews · doi:10.1152/physrev.00033.2015 · Cited by 860 · see citing works
Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development.
Gu, C.-H., Rodríguez, E., Reimert, D. V., Shu, T., Fritzsch, B., Richards, L. J., Kolodkin, A., & Ginty, D. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00169-2 · Cited by 756 · see citing works
Osteoprotection by semaphorin 3A
Hayashi, M., Nakashima, T., Taniguchi, M., Kodama, T., Kumanogoh, A., & Takayanagi, H. (2012) · Nature · doi:10.1038/nature11000 · Cited by 606 · see citing works
Self-citationDisruption of Semaphorin III/D Gene Causes Severe Abnormality in Peripheral Nerve Projection
Taniguchi, M., Yuasa, S., Fujisawa, H., Naruse, I., Saga, S., Mishina, M., & Yagi, T. (1997) · Neuron · doi:10.1016/s0896-6273(00)80368-2 · Cited by 516 · see citing works
Mizoguchi, T., Pinho, S., Ahmed, J. U., Kunisaki, Y., Hanoun, M., Mendelson, A., Ono, N., Kronenberg, H. M., & Frenette, P. S. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.03.013 · Cited by 441 · see citing works
Sema3A regulates bone-mass accrual through sensory innervations
Fukuda, T., Takeda, S., Xu, R., Ochi, H., Sunamura, S., Sato, T., Shibata, S., Yoshida, Y., Gu, Z., Kimura, A., et al. (2013) · Nature · doi:10.1038/nature12115 · Cited by 416 · see citing works
DMP1-targeted Cre Expression in Odontoblasts and Osteocytes
Lu, Y., Xie, Y., Zhang, S., Dusevich, V., Bonewald, L. F., & Feng, J. Q. (2007) · Journal of Dental Research · doi:10.1177/154405910708600404 · Cited by 350 · see citing works
Cohort Profile: Research on Osteoarthritis/Osteoporosis Against Disability study
Yoshimura, N., Muraki, S., Oka, H., Kawaguchi, H., Nakamura, K., & Akune, T. (2009) · International Journal of Epidemiology · doi:10.1093/ije/dyp276 · Cited by 267 · see citing works
Self-citationWoo, S. M., Rosser, J., Dusevich, V., Kalajzic, I., & Bonewald, L. F. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.465 · Cited by 243 · see citing works
Osteocytic signalling pathways as therapeutic targets for bone fragility
Plotkin, L. I., & Bellido, T. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.71 · Cited by 206 · see citing works
Frost, H. M. (1960) · Journal of Bone and Joint Surgery · doi:10.2106/00004623-196042010-00011 · Cited by 193 · see citing works
Nishikawa, K., Nakashima, T., Takeda, S., Isogai, M., Hamada, M., Kimura, A., Kodama, T., Yamaguchi, A., Owen, M. J., Takahashi, S., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42528 · Cited by 180 · see citing works
Self-citationDole, N. S., Mazur, C. M., Acevedo, C., Lopez, J. P., Monteiro, D. A., Fowler, T. W., Gludovatz, B., Walsh, F., Regan, J. N., Messina, S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.115 · Cited by 173 · see citing works
In vitro and in vivo approaches to study osteocyte biology
Kalajzić, I., Matthews, B. G., Torreggiani, E., Harris, M. A., Pajevic, P. D., & Harris, S. E. (2012) · Bone · doi:10.1016/j.bone.2012.09.040 · Cited by 161 · see citing works
Update on Estrogens and the Skeleton
Khosla, S. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0856 · Cited by 159 · see citing works
Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice
Windahl, S. H., Börjesson, A. E., Farman, H. H., Engdahl, C., Movérare-Skrtic, S., Sjögren, K., Lagerquist, M. K., Kindblom, J. M., Koskela, A., Tuukkanen, J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220811110 · Cited by 136 · see citing works
The Role of Osteocytes in Age-Related Bone Loss
Jilka, R. L., & O’Brien, C. A. (2016) · Current Osteoporosis Reports · doi:10.1007/s11914-016-0297-0 · Cited by 136 · see citing works
Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice
Kondoh, S., Inoue, K., Igarashi, K., Sugizaki, H., Shirode-Fukuda, Y., Inoue, E., Yu, T., Takeuchi, J., Kanno, J., Bonewald, L. F., et al. (2013) · Bone · doi:10.1016/j.bone.2013.12.005 · Cited by 119 · see citing works
Marathe, N., Rangaswami, H., Zhuang, S., Boss, G. R., & Pilz, R. B. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.294959 · Cited by 82 · see citing works
Cyclic GMP-Gated CNG Channels Function in Sema3A-Induced Growth Cone Repulsion
Togashi, K., von Schimmelmann, M. J., Nishiyama, M., Lim, C., Yoshida, N., Yun, B., Molday, R. S., Goshima, Y., & Hong, K. (2008) · Neuron · doi:10.1016/j.neuron.2008.03.017 · Cited by 80 · see citing works
A method for isolating high quality RNA from mouse cortical and cancellous bone
Kelly, N. H., Schimenti, J. C., Ross, F. P., & van der Meulen, M. C. H. (2014) · Bone · doi:10.1016/j.bone.2014.07.022 · Cited by 69 · see citing works
Stimulators and activators of soluble guanylate cyclase for urogenital disorders
Mónica, F. Z., & Antunes, E. (2017) · Nature Reviews Urology · doi:10.1038/nrurol.2017.181 · Cited by 57 · see citing works
Isolation of Mouse Osteocytes Using Cell Fractionation for Gene Expression Analysis
Halleux, C. M., Krämer, I., Allard, C., & Kneissel, M. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-415-5_5 · Cited by 35 · see citing works
Hwang, J., Lee, J. Y., Park, M. H., Kim, K. S., Kim, K. K., Ryu, H. J., Lee, J. Y., Han, B. G., Kim, J. W., Oh, B., et al. (2006) · Osteoporosis International · doi:10.1007/s00198-006-0126-x · Cited by 29 · see citing works
Liu, D., Lü, N., Zhao, L., Zhang, M.-J., Tao, B., Xuan, Y., Sun, L., Zhao, H., Wang, W., Liu, J., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1443 · Cited by 16 · see citing works
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Andreev, D., Liu, M., Weidner, D., Kachler, K., Faas, M., Grüneboom, A., Schlötzer-Schrehardt, U., Muñoz, L. E., Steffen, U., Grötsch, B., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134214 · Cited by 188 · see citing works
Osteoimmunology: A Current Update of the Interplay Between Bone and the Immune System
Guder, C., Gravius, S., Burger, C., Wirtz, D. C., & Schildberg, F. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00058 · Cited by 192 · see citing works
Lin, Z., He, H., Wang, M., & Liang, J. (2019) · Cell Proliferation · doi:10.1111/cpr.12688 · Cited by 187 · see citing works
Targeting strategies for bone diseases: signaling pathways and clinical studies
Xu, H., Wang, W., Liu, X., Huang, W. H., Chen, Z., Xu, Y., Yang, H., Bai, J., & Geng, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01467-8 · Cited by 173 · see citing works
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Lu, L., & Tian, L. (2023) · Journal of Endocrinology · doi:10.1530/joe-23-0116 · Cited by 163 · see citing works
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Ru, J., & Wang, Y.-F. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03059-8 · Cited by 149 · see citing works
Behera, J., Kumar, A., Voor, M. J., & Tyagi, N. (2021) · Theranostics · doi:10.7150/thno.58410 · Cited by 148 · see citing works
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Zhou, R., Guo, Q., Xiao, Y., Guo, Q., Huang, Y., Li, C., & Luo, X. (2021) · Bone Research · doi:10.1038/s41413-021-00142-4 · Cited by 147 · see citing works
The origins and roles of osteoclasts in bone development, homeostasis and repair
Yahara, Y., Nguyen, T., Ishikawa, K., Kamei, K., & Alman, B. A. (2022) · Development · doi:10.1242/dev.199908 · Cited by 107 · see citing works
Wu, X., Li, F., Dang, L., Liang, C., Lü, A., & Zhang, G. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00076 · Cited by 103 · see citing works
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Wang, J. S., Kamath, T., Mazur, C. M., Mirzamohammadi, F., Rotter, D., Hojo, H., Castro, C. D., Tokavanich, N., Patel, R., Govea, N., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26571-7 · Cited by 103 · see citing works
Liu, H., Yi, X., Tu, S., Cheng, C., & Luo, J. F. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111074 · Cited by 90 · see citing works
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Guo, Y., Su, T., Yang, M., Li, C., Guo, Q., Xiao, Y., Huang, Y., Liu, Y., & Luo, X. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30111 · Cited by 79 · see citing works
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Li, Y., Zhang, Y., Li, X., Yi, S. S., & Xu, J. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.03.009 · Cited by 64 · see citing works
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Shen, G., Ren, H. J., Shang, Q., Zhang, Z., Zhao, W., Yu, X., Tang, J., Yang, Z., Liang, D., & Jiang, X. (2020) · Theranostics · doi:10.7150/thno.42982 · Cited by 54 · see citing works
Ophiopogonin D promotes bone regeneration by stimulating CD31hiEMCNhi vessel formation
Yang, M., Li, C., Xiao, Y., Guo, Q., Huang, Y. H., Su, T., Luo, X., & Jiang, T. (2020) · Cell Proliferation · doi:10.1111/cpr.12784 · Cited by 52 · see citing works
Mulati, M., Kobayashi, Y., Takahashi, A., Numata, H., Saito, M., Hiraoka, Y., Ochi, H., Sato, S., Ezura, Y., Yuasa, M., et al. (2019) · Bone · doi:10.1016/j.bone.2019.115076 · Cited by 47 · see citing works
Sonoda, S., Murata, S., Nishida, K., Kato, H., Uehara, N., Kyumoto‐Nakamura, Y., Yamaza, H., Takahashi, I., Kukita, T., & Yamaza, T. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01818-0 · Cited by 46 · see citing works
Estrogen and bones after menopause: a reappraisal of data and future perspectives
Anagnostis, P. G., Bosdou, J. Κ., Vaitsi, K., Goulis, D. G., & Lambrinoudaki, I. V. (2020) · HORMONES · doi:10.1007/s42000-020-00218-6 · Cited by 45 · see citing works
Pathophysiological mechanism of acute bone loss after fracture
Zheng, X.-Q., Huang, J., Lin, J., & Song, C. (2022) · Journal of Advanced Research · doi:10.1016/j.jare.2022.08.019 · Cited by 43 · see citing works
Sema3A secreted by sensory nerve induces bone formation under mechanical loads
Mei, H., Li, Z., Lv, Q., Li, X., Wu, Y., Feng, Q., Jiang, Z., Zhou, Y., Zheng, Y., Gao, Z., et al. (2024) · International Journal of Oral Science · doi:10.1038/s41368-023-00269-6 · Cited by 40 · see citing works
Neuronal guidance genes in health and diseases
Yuasa‐Kawada, J., Kinoshita-Kawada, M., Tsuboi, Y., & Wu, J. Y. (2022) · Protein & Cell · doi:10.1093/procel/pwac030 · Cited by 36 · see citing works
Park, K., Park, J.-I., Lee, S., Yoo, K., Kweon, G., Kwon, I. K., Yun, H., & Hong, J. T. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106423 · Cited by 36 · see citing works
The IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis
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Self-citationIdentification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss
Xu, R., Shen, X., Xie, H., Zhang, H., Liu, D., Chen, X., Fu, Y., Zhang, P., Yang, Y. A., Cheng, J., et al. (2021) · Theranostics · doi:10.7150/thno.55041 · Cited by 36 · see citing works
Tsuchiya, Y., Hayashi, M., Nagamatsu, K., Ono, T., Kamakura, M., Iwata, T., & Nakashima, T. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013821 · Cited by 34 · see citing works
Self-citationSchurman, C. A., Burton, J. B., Rose, J., Ellerby, L., Alliston, T. N., & Schilling, B. (2023) · Journal of Bone Metabolism · doi:10.11005/jbm.2023.30.1.1 · Cited by 33 · see citing works
Plotkin, L. I., & Wallace, J. M. (2021) · Bone · doi:10.1016/j.bone.2021.115994 · Cited by 32 · see citing works
Axon guidance molecules in immunometabolic diseases
Nakanishi, Y., Kang, S., & Kumanogoh, A. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-021-00189-0 · Cited by 31 · see citing works
Kisspeptin and neurokinin B: roles in reproductive health
Koysombat, K., Tsoutsouki, J., Patel, A., Comninos, A. N., Dhillo, W. S., & Abbara, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00015.2024 · Cited by 35 · see citing works
Different Effects of Fluoride Exposure on the Three Major Bone Cell Types
Jiang, N., Guo, F., Sun, B., Zhang, X., & Xu, H. J. (2019) · Biological Trace Element Research · doi:10.1007/s12011-019-01684-9 · Cited by 29 · see citing works
Regulation of bone marrow mesenchymal stem cell fate by long non-coding RNA
Guo, Q., Guo, Q., Xiao, Y., Li, C., Huang, Y., & Luo, X. (2020) · Bone · doi:10.1016/j.bone.2020.115617 · Cited by 32 · see citing works
Jin, Y., Zhou, B.-H., Zhao, J., Ommati, M. M., Wang, S., & Wang, H. (2023) · Environmental Pollution · doi:10.1016/j.envpol.2023.122407 · Cited by 29 · see citing works
Huang, Y., Wan, S., & Yang, M. H. (2021) · Biology Direct · doi:10.1186/s13062-021-00302-w · Cited by 28 · see citing works
The emerging role of miR‐128 in musculoskeletal diseases
Shang, Q., Shen, G., Chen, G., Zhang, Z., Yu, X., Zhao, W., Zhang, P., Chen, H., Tang, K., Yu, F., et al. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30179 · Cited by 26 · see citing works
Ono, T., & Nakashima, T. (2022) · Journal of Oral Biosciences · doi:10.1016/j.job.2022.01.008 · Cited by 26 · see citing works
Self-citationLi, Y., Hu, M., Xie, J., Li, S., & Dai, L. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03393-6 · Cited by 26 · see citing works
Effects of Innervation on Angiogenesis and Osteogenesis in Bone and Dental Tissue Engineering
Xiao, L., Zhu, M., Yu, K., Zhang, Q., Dai, Z., Weir, M. D., Zhao, Z., Bai, Y., Schneider, A., Oates, T. W., et al. (2024) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2023.0267 · Cited by 25 · see citing works
Ma, X., Bian, Y., Yuan, H., Chen, N., Pan, Y., Zhou, W., Gao, S., Du, X. Z., Hao, S., Yan, Z., et al. (2020) · Aging · doi:10.18632/aging.103277 · Cited by 25 · see citing works
Ootake, T., Ishii, T., Sueishi, K., Watanabe, A., Ishizuka, Y., Amano, K., Nagao, M., Nishimura, K., & Nishii, Y. (2021) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2021.08.005 · Cited by 25 · see citing works
Cao, Y., Li, L., & Fan, Z. (2021) · Cell Proliferation · doi:10.1111/cpr.13032 · Cited by 23 · see citing works
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Wang, J. S., & Wein, M. N. (2022) · Current Osteoporosis Reports · doi:10.1007/s11914-022-00753-8 · Cited by 24 · see citing works
Suo, J., Gan, Y., Xie, Y., Xu, S., Wang, J., Chen, D., Chen, L., Deng, L., Feng, S., Han, J. J., et al. (2023) · Life Medicine · doi:10.1093/lifemedi/lnad045 · Cited by 22 · see citing works
Exosomes in bone remodeling and breast cancer bone metastasis
Murari, L. S. S., Krishnan, R., Akshaya, R. L., Das, U. R., Satishkumar, S., & Selvamurugan, N. (2022) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2022.09.008 · Cited by 21 · see citing works
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Wu, J., Niu, L., Yang, K., Xu, J., Zhang, D., Ling, J., Xia, P., Wu, Y., Liu, X., Liu, J., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102234 · Cited by 22 · see citing works
Li, D., Liu, J., Yang, C., Tian, Y. E., Yin, C., Hu, L., Chen, Z., Zhao, F., Zhang, R., Lü, A., et al. (2021) · Theranostics · doi:10.7150/thno.54477 · Cited by 21 · see citing works
TNF-α promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis
Cui, H., Li, J., Li, X., Su, T., Wen, P., Wang, C., Deng, X., Fu, Y., Zhao, W., Li, C., et al. (2024) · Bone · doi:10.1016/j.bone.2024.117050 · Cited by 20 · see citing works
Yeh, P.-S., Chen, J., Cherng, Y., Yang, S., Tai, Y., & Chen, R. (2020) · Molecules · doi:10.3390/molecules25122876 · Cited by 20 · see citing works
Jiménez-Ortega, R. F., Ortega-Meléndez, A. I., Patiño, N., Rivera‐Paredez, B., Hidalgo‐Bravo, A., & Velázquez‐Cruz, R. (2024) · Biology · doi:10.3390/biology13070505 · Cited by 19 · see citing works
UBE2E3 regulates cellular senescence and osteogenic differentiation of BMSCs during aging
Liu, Y., Cai, G., Chen, P., Jiang, T., & Xia, Z. (2021) · PeerJ · doi:10.7717/peerj.12253 · Cited by 18 · see citing works
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Şen, S., Lux, C. J., & Erber, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158297 · Cited by 18 · see citing works
Crosstalk between axon guidance signaling and bone remodeling
Nakanishi, Y., Kang, S., & Kumanogoh, A. (2021) · Bone · doi:10.1016/j.bone.2021.116305 · Cited by 18 · see citing works
Positive Effect of Gushukang on Type-H Vessel and Bone Formation
Li, W., Zhou, X., Jiang, T.-J., He, H., & Wen, T. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00265 · Cited by 17 · see citing works
Osteoblast Lineage Cell-derived Sema3A Regulates Bone Homeostasis Independently of Androgens
Yamashita, Y., Hayashi, M., Saito, M., & Nakashima, T. (2022) · Endocrinology · doi:10.1210/endocr/bqac126 · Cited by 16 · see citing works
Self-citationZhai, X., Zhou, J., Huang, X., Weng, J., Lin, H., Sun, S., Chi, J., & Meng, L. (2024) · Scientific Reports · doi:10.1038/s41598-024-70151-w · Cited by 16 · see citing works
Osteoimmunology — Bidirectional dialogue and inevitable union of the fields of bone and immunity —
Takayanagi, H. (2020) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.96.013 · Cited by 16 · see citing works
Self-citationSatomi, K., Nishimura, K., & Igarashi, K. (2022) · Journal of Periodontal Research · doi:10.1111/jre.13038 · Cited by 16 · see citing works
Jin, X., Xu, J., Yang, F., Chen, J., Luo, F., Xu, B., & Xu, J. (2023) · Calcified Tissue International · doi:10.1007/s00223-023-01080-5 · Cited by 15 · see citing works
Azab, E., Chandler, K. B., Uda, Y., Sun, N., Hussein, A. I., Shuwaikan, R., Lu, V., Costello, C. E., McComb, M. E., & Pajevic, P. D. (2020) · The FASEB Journal · doi:10.1096/fj.202000366r · Cited by 15 · see citing works
Zhu, W., Ming, P., Zhang, S., & Qiu, J. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11575 · Cited by 15 · see citing works
The Osteocyte Transcriptome: Discovering Messages Buried Within Bone
Wee, N. K. Y., Sims, N. A., & Morello, R. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-021-00708-5 · Cited by 15 · see citing works
Relationship between GDF15 level and bone metabolism in postmenopausal Chinese women
Li, W., Li, C., Zhou, X., Jiang, T., Guo, L., & Liu, H. (2020) · Gynecological Endocrinology · doi:10.1080/09513590.2020.1764929 · Cited by 14 · see citing works
Fu, Y., Wang, J., Schroyen, M., Chen, G., Zhang, H., Wu, S., Li, B., & Qi, G. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.962330 · Cited by 14 · see citing works
Shang, Q., Zhao, W., Shen, G., Yu, X., Zhang, Z., Huang, X., Qin, W., Chen, G., Yu, F., Tang, K., et al. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/1517596 · Cited by 14 · see citing works
Effect of ovariectomy induced osteoporosis on metaphysis and diaphysis repair process
Inoue, S., Fujikawa, K., Matsuki-Fukushima, M., & Nakamura, M. (2021) · Injury · doi:10.1016/j.injury.2021.02.020 · Cited by 14 · see citing works
Wu, K.-L., Huang, D., & Huang, X. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1321151 · Cited by 13 · see citing works
MiR-379-5p aggravates experimental autoimmune uveitis in mice via the regulation of SEMA3A
Li, M., Gao, X., Liu, K., Bao, N., & Jiang, Z. (2021) · Autoimmunity · doi:10.1080/08916934.2021.1931841 · Cited by 13 · see citing works
Su, J.-W., Li, S., Tao, J., Xu, Y., Wang, K., Qian, X., Deng, G., Peng, X., & Chen, F. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174381 · Cited by 13 · see citing works
Exosomes derived from osteoclasts under compression stress inhibit osteoblast differentiation
WANG, Y., Zheng, Y., & Li, W. (2021) · Biocell · doi:10.32604/biocell.2021.013960 · Cited by 13 · see citing works
Han, X., Zhu, N., Wang, Y., & Cheng, G. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11619 · Cited by 12 · see citing works
Kim, S., Mun, S., Shin, W., Han, K., & Kim, M. Y. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11082145 · Cited by 12 · see citing works
Wang, R., Zhang, M., Hu, Y., He, J., Lin, Q., & Peng, N. (2022) · Human Cell · doi:10.1007/s13577-022-00764-8 · Cited by 12 · see citing works
Yuze, M., Hu, J., Lv, J., Cheng, X., Tianwen, X., & Junqiang, Z. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1629273 · Cited by 11 · see citing works
Li, J., Wang, T., Li, C. V., Wang, Z., Li, S., Ma, L., & Zheng, L. (2020) · Chinese Medical Journal · doi:10.1097/cm9.0000000000000612 · Cited by 11 · see citing works
The interplay between the nerves and skeleton: a 30-year bibliometric analysis
Mei, H., Wu, Y., Feng, Q., Li, X., Zhou, J., Jiang, F., Huang, S., & Li, J. (2023) · Annals of Translational Medicine · doi:10.21037/atm-22-3323 · Cited by 10 · see citing works
The Timing Sequence and Mechanism of Aging in Endocrine Organs
He, Y., Fang, B., Wang, Z., Chen, Y., & Dong, Y. (2023) · Cells · doi:10.3390/cells12070982 · Cited by 12 · see citing works
Wen, X.-H., Zhang, J., Yang, W., Nie, X., Gui, R., Shan, D., Huang, R., & Deng, H. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.9786 · Cited by 11 · see citing works
SEMA7A: A glycoprotein with therapeutic potential in inflammatory diseases and tumor development
Huang, Q., Wang, Y., Zhang, Z., Yang, Y., Li, H., & Chen, L. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.144907 · Cited by 10 · see citing works
Pathophysiology of bone remodelling cycle: Role of immune system and lipids
Parolini, C. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116844 · Cited by 10 · see citing works
Ozawa, M., Hirawa, N., Haze, T., Haruna, A., Kawano, R., Komiya, S., Ohki, Y., Suzuki, S., Kobayashi, Y., Fujiwara, A., et al. (2022) · Clinical and Experimental Nephrology · doi:10.1007/s10157-022-02308-8 · Cited by 10 · see citing works
Han, X., Ma, Y., Lu, W., Yan, J., Qin, W., He, J., Niu, L., & Jiao, K. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1138601 · Cited by 9 · see citing works
Semaphorin 3A on Osteoporosis: An Overreview of the Literature
Zhang, Y., Shi, H., Dai, X., Shen, J., Yin, J., Xu, T., Yue, G., Guo, H., Liang, R., Chen, Q., et al. (2025) · Calcified Tissue International · doi:10.1007/s00223-025-01350-4 · Cited by 9 · see citing works
Yang, M., Zhang, M., Li, Z., Liu, J., Li, Y., Yang, Z., Wang, X., Huang, X., Yu, B., Hou, J., et al. (2023) · Genomics · doi:10.1016/j.ygeno.2023.110573 · Cited by 9 · see citing works
Regulation of the Osteocyte Secretome with Aging and Disease
Kitase, Y., & Prideaux, M. (2023) · Calcified Tissue International · doi:10.1007/s00223-023-01089-w · Cited by 9 · see citing works
Ubuzima, P., Nshimiyimana, E., Mukeshimana, C., Mazimpaka, P., Mugabo, E., Mbyayingabo, D., Mohamed, A. S., & Habumugisha, J. (2024) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2024.152286 · Cited by 9 · see citing works
Osteoclastogenesis inhibition by mutated IGSF23 results in human osteopetrosis
Yuan, Y., Yang, L., Liu, T., Zhang, H., & Lu, Q. (2019) · Cell Proliferation · doi:10.1111/cpr.12693 · Cited by 9 · see citing works
Wang, C., Dong, L., Wang, Y., Jiang, Z., Zhang, J., & Yang, G. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.750827 · Cited by 9 · see citing works
Kalyanaraman, H., China, S. P., Cabriales, J. A., Moininazeri, J., Casteel, D. E., Garcia, J. J., Wong, V. W., Chen, A., Sah, R. L., Boss, G. R., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4746 · Cited by 9 · see citing works
Ren, Q., Chen, K., & Wang, L. (2025) · Letters in Drug Design & Discovery · doi:10.1016/j.lddd.2025.100027 · Cited by 8 · see citing works
Tissue-specific mechanism of estrogen in osteoporosis and vascular calcification
Wu, W., Qiao, A., & Du, T. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177783 · Cited by 8 · see citing works
- Authors
- Hayashi, M., Nakashima, T., Yoshimura, N., Okamoto, K., Tanaka, S., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- The University of Tokyo (JP)
- Corresponding author
- Nakashima, Tomoki
- Takayanagi, Hiroshi
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 29
- Issue
- 3
- Pages
- 627-637.e5
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2910201788
- Cited by
- 156
- References
- 35
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 22 · 2023: 20 · 2022: 26 · 2021: 28 · 2020: 27 · 2019: 6
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Science and Technology Agency (JPMJPR13MC)
- CREST
- AMED (JP17gm0810003)
- Japan Society for the Promotion of Science
- Mochida Memorial Foundation
- Terumo Foundation
- Life Science Foundation of Japan
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ichiro Kanehara Foundation
- Kanazawa Medical Research Foundation
- Naito Foundation
- Nakatomi Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Sumitomo Foundation
- Asahi Glass Foundation
- Mitsui Life Social Welfare Foundation
- Daiichi Sankyo Foundation
- ONO Medical Research Foundation
- Secom Science and Technology Foundation
- Chugai Pharmaceutical
- AYUMI Pharmaceutical Corporation
- Noevir Co., Ltd
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Medicinal Plant Pharmacodynamics Research
- Keywords
- semaphorin 3A, osteocytes, estrogen, bone aging, menopause, osteoporosis, bone homeostasis, osteocyte survival, neuropilin-1, ovariectomy, bone loss
- MeSH terms
- Aging, Animals, Bone Resorption, Estrogens, Female, Humans, Menopause, Mice, Inbred C57BL, Middle Aged, Osteocytes, Osteogenesis, Neuropilin-1, Semaphorin-3A, Mice, HEK293 Cells
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