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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

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–cell contact. This indirect effect leads to activation of osteoblastic bone formation, and inhibition of osteoclastic bone resorption.(Credit, Osaka University)　

Despite what some people think, bone is not merely a passive component of the body. The skeleton is structurally dynamic and responds to life’s 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—secretory leukocyte protease inhibitor (SLPI)—that helps mediate this critical balance, which could be used in the development of new treatments for bone diseases such as osteoporosis.

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—its 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.

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 in vivo. Akito Morimoto, lead author, explains the research methodology of the new study published in Nature Communications: “We could establish that PTH highly upregulates the gene Slpi in osteoblasts in animal models. We analyzed the bone phenotype of experimental mice in which the gene was ‘knocked out’ and showed that genetic modification of Slpi prevented PTH from inducing bone formation. Moreover, Slpi induction in osteoblasts themselves increased their differentiation while promoting osteoblast–osteoclast contact which reduces bone loss activity.” Furthermore, biomicroscopic imaging in living bone demonstrated that SLPI secreted outside the cells is essential for association between osteoblasts and osteoclasts and the cell–cell interactions that PTH mediates.

Corresponding author Junichi Kikuta summarizes their results. “Our 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.”

“A clear understanding of the cellular networks and molecular pathways that mediate PTH anabolism will enhance clinical applicability of this drug,” senior author Masaru Ishii explains. “Moreover, it may inform the development of innovative pharmacotherapies for managing osteoporosis and other intractable orthopedic diseases.”

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The article, “SLPI is a critical mediator that controls PTH-induced bone formation” was published in Nature Communications at DOI: https://doi.org/10.1038/s41467-021-22402-x

Keywords: Medicine/Health
Secondary keywords: Orthopedic Medicine, Endocrinology, Internal Medicine, Molecular Biology, Genes

Summary: 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.

Tweet: SLPI balances bone formation with resorption to fine-tune the action of PTH
Tweet 2: Researchers at Osaka University reveal how SLPI harmonizes the mutually antagonistic actions of parathyroid hormone on bone
Tweet 3: OsakaU researchers identify the bare bones of skeletal tissue formation

Figure 2 :Representative micro-computed tomography images of the femurs. Note that the anabolic effect of PTH was absent in Slpi-KO mice. These data demonstrate that the effect of PTH on bone is dependent on SLPI. Scale bar, 1000 µm. (Credit, Osaka University)　

Figure 3 : Intravital imaging of osteoblasts and osteoclasts in wild-type and Slpi-KO mice. Note that the number of dynamic osteoblast–osteoclast contact events after PTH treatment was decreased in Slpi-KO mice. Cyan, mature osteoblasts; red, mature osteoclasts. Contact areas (yellow) were defined as the areas of osteoblast and osteoclast colocalization. Scale bar, 200 µm.  (Credit, Osaka University)　

Title: “SLPI is a critical mediator that controls PTH-induced bone formation”
Journal: Nature Communications
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
DOI: 10.1038/s41467-021-22402-x
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