{"id":6684,"date":"2021-04-09T13:37:15","date_gmt":"2021-04-09T04:37:15","guid":{"rendered":"https:\/\/www.med.osaka-u.ac.jp\/eng\/?page_id=6684"},"modified":"2022-08-26T14:43:40","modified_gmt":"2022-08-26T05:43:40","slug":"ishii04","status":"publish","type":"page","link":"https:\/\/www.med.osaka-u.ac.jp\/eng\/activities\/results\/2021year\/ishii04","title":{"rendered":"Akito Morimoto,  Junichi Kikuta, Masaru Ishii \u226aImmunology and Cell Biology\u226b <span>Balancing between build-up and break-down of bone<\/span>"},"content":{"rendered":"<ul class=\"linkBar clearfix\">\n<li><a href=\"https:\/\/www.med.osaka-u.ac.jp\/activities\/results\/2021year\/ishii04122021\">Text in Japanese<\/a><\/li>\n<\/ul>\n<p><em><\/p>\n<p><span class=\"lineFrame\">Publish\u00a0<\/span> <em>Nature Communications<\/em><\/p>\n<p><em><br \/>Researchers at Osaka University define the complex role of SLPI, a secretory leukocyte protease inhibitor, in coordinating the biphasic action of parathyroid hormone on the metabolism of bone<br \/><\/em><\/p>\n<p class=\"figure\"><a href=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic1.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-6685 size-medium\" src=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic1-331x400.jpg?_t=1633580283\" alt=\"\" width=\"331\" height=\"400\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic1-331x400.jpg 331w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic1-847x1024.jpg 847w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic1-768x929.jpg 768w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic1.jpg 1035w\" sizes=\"(max-width: 331px) 100vw, 331px\" \/><\/a><\/p>\n<p>Figure 1 : PTH binding to PTH receptor (PTH1R) upregulates SLPI expression. SLPI directly acts in osteoblasts to enhance bone formation by controlling gene expression. Additionally, SLPI promotes the adhesion of osteoblasts to neighboring osteoclasts, thereby increasing direct cell\u2013cell contact. This indirect effect leads to activation of osteoblastic bone formation, and inhibition of osteoclastic bone resorption.(Credit, Osaka University)\u3000<\/p>\n<p>Despite what some people think, bone is not merely a passive component of the body. The skeleton is structurally dynamic and responds to life\u2019s physical stresses with continual equilibration between bone mass loss and reformation. This ensures healing and remodeling in tune with the ebb and flow of calcium and phosphorus in the bloodstream. Now, researchers at Osaka university have identified a molecule\u2014secretory leukocyte protease inhibitor (SLPI)\u2014that helps mediate this critical balance, which could be used in the development of new treatments for bone diseases such as osteoporosis.<\/p>\n<p>Skeletal tissue changes are orchestrated primarily by parathyroid hormone (PTH), a regulator of blood calcium levels that is secreted by the parathyroid glands in the neck. PTH is known to have a dual effect on bone\u2014its action is primarily catabolic, causing bone dissolution and removal. However, in small intermittent doses, PTH can also increase bone mass (anabolic). Though PTH has long been used for the clinical treatment of osteoporosis, the precise mechanism and pathways whereby PTH promotes bone formation are poorly understood.<\/p>\n<p>The researchers looked at the interactions between cells that mediate bone formation (osteoblasts), cells that mediate bone loss (osteoclasts) and the functional role of SLPI in bone metabolism <em>in vivo<\/em>. Akito Morimoto, lead author, explains the research methodology of the new study published in <em>Nature Communications<\/em>: \u201cWe could establish that PTH highly upregulates the gene <em>Slpi<\/em> in osteoblasts in animal models. We analyzed the bone phenotype of experimental mice in which the gene was \u2018knocked out\u2019 and showed that genetic modification of <em>Slpi <\/em>prevented PTH from inducing bone formation. Moreover, <em>Slpi<\/em> induction in osteoblasts themselves increased their differentiation while promoting osteoblast\u2013osteoclast contact which reduces bone loss activity.\u201d Furthermore, biomicroscopic imaging in living bone demonstrated that SLPI secreted outside the cells is essential for association between osteoblasts and osteoclasts and the cell\u2013cell interactions that PTH mediates.<\/p>\n<p>Corresponding author Junichi Kikuta summarizes their results. \u201cOur findings clarify the roles of SLPI as a novel coupling factor and coordinator of bone remodeling for conservation of mass, strength and structural integrity. Not only does it promote bone formation by osteoblasts, it also attracts osteoclasts closer to osteoblasts to suppress bone loss.\u201d<\/p>\n<p>\u201cA clear understanding of the cellular networks and molecular pathways that mediate PTH anabolism will enhance clinical applicability of this drug,\u201d senior author Masaru Ishii explains. \u201cMoreover, it may inform the development of innovative pharmacotherapies for managing osteoporosis and other intractable orthopedic diseases.\u201d<\/p>\n<p>###<\/p>\n<p>The article, \u201cSLPI is a critical mediator that controls PTH-induced bone formation\u201d was published in <em>Nature Communications<\/em> at DOI: https:\/\/doi.org\/10.1038\/s41467-021-22402-x<\/p>\n<p><strong>Keywords: <\/strong>Medicine\/Health<br \/><strong>Secondary keywords:<\/strong> Orthopedic Medicine, Endocrinology, Internal Medicine, Molecular Biology, Genes<\/p>\n<p><strong>Summary:<\/strong> Researchers at Osaka University have shown that SLPI, a secretory leukocyte protease inhibitor, coordinates the mutually contradictory actions of parathyroid hormone (PTH) on bone. They revealed the genetic mechanisms and molecular pathways whereby SLPI promotes osteoblast activity to augment bone mass and showed how osteoblasts interact with osteoclasts to subdue bone resorption. This knowledge will inform clinical usage of anabolic PTH in osteoporosis as well as promote development of innovative drugs.<\/p>\n<p><strong>Tweet: <\/strong>SLPI balances bone formation with resorption to fine-tune the action of PTH<br \/><strong>Tweet 2:<\/strong> Researchers at Osaka University reveal how SLPI harmonizes the mutually antagonistic actions of parathyroid hormone on bone<br \/><strong>Tweet 3: <\/strong>OsakaU researchers identify the bare bones of skeletal tissue formation<\/p>\n<p class=\"figure\"><a href=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic2.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-6694 size-medium\" src=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic2-400x172.jpg?_t=1633581244\" alt=\"\" width=\"400\" height=\"172\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic2-400x172.jpg 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic2-768x331.jpg 768w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic2.jpg 912w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><\/a><\/p>\n<p>Figure 2 :Representative micro-computed tomography images of the femurs. Note that the anabolic effect of PTH was absent in <em>Slpi<\/em>-KO mice. These data demonstrate that the effect of PTH on bone is dependent on SLPI. Scale bar, 1000 \u00b5m. (Credit, Osaka University)\u3000<\/p>\n<p class=\"figure\"><a href=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic3.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-6695 size-medium\" src=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic3-400x267.jpg?_t=1633581312\" alt=\"\" width=\"400\" height=\"267\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic3-400x267.jpg 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2021\/10\/ishii-pic3.jpg 694w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><\/a><\/p>\n<p>Figure 3 : Intravital imaging of osteoblasts and osteoclasts in wild-type and <em>Slpi<\/em>-KO mice. Note that the number of dynamic osteoblast\u2013osteoclast contact events after PTH treatment was decreased in <em>Slpi<\/em>-KO mice. Cyan, mature osteoblasts; red, mature osteoclasts. Contact areas (yellow) were defined as the areas of osteoblast and osteoclast colocalization. Scale bar, 200\u2009\u00b5m.\u00a0\u00a0(Credit, Osaka University)\u3000<\/p>\n<p>Title: \u201cSLPI is a critical mediator that controls PTH-induced bone formation\u201d<br \/>Journal: <em>Nature Communications<br \/><\/em>Authors: Akito Morimoto, Junichi Kikuta, Keizo Nishikawa, Takao Sudo, Maki Uenaka, Masayuki Furuya, Tetsuo Hasegawa, Kunihiko Hashimoto, Hiroyuki Tsukazaki, Shigeto Seno, Akira Nakamura, Daisuke Okuzaki, Fuminori Sugihara, Akinori Ninomiya, Takeshi Yoshimura, Ryoko Takao-Kawabata, Hideo Matsuda, Masaru Ishii<br \/>DOI: 10.1038\/s41467-021-22402-x<br \/>Funded by: Japan Science and Technology Agency, Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Text in Japanese Publish\u00a0 Nature Communications Researchers at Osaka University define the complex role of SLP [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":6685,"parent":6480,"menu_order":80,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"_links":{"self":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6684"}],"collection":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/comments?post=6684"}],"version-history":[{"count":21,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6684\/revisions"}],"predecessor-version":[{"id":7572,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6684\/revisions\/7572"}],"up":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6480"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/media\/6685"}],"wp:attachment":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/media?parent=6684"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}