Syndecan‐3 enhances anabolic bone formation through WNT signaling
Osteoporosis is the most common age‐related metabolic bone disorder, which is characterized by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone st...
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creator | Johnson de Sousa Brito, Francesca Manuela Butcher, Andrew Pisconti, Addolorata Poulet, Blandine Prior, Amanda Charlesworth, Gemma Sperinck, Catherine Scotto di Mase, Michele Liu, Ke Bou‐Gharios, George Jurgen van 't Hof, Robert Daroszewska, Anna |
description | Osteoporosis is the most common age‐related metabolic bone disorder, which is characterized by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however, anabolic therapeutics are few and their use is time restricted. Here, we report that Syndecan‐3 increases new bone formation through enhancement of WNT signaling in osteoblasts. Young adult Sdc3−/− mice have low bone volume, reduced bone formation, increased bone marrow adipose tissue, increased bone fragility, and a blunted anabolic bone formation response to mechanical loading. This premature osteoporosis‐like phenotype of Sdc3−/− mice is due to delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast‐mediated bone resorption. Indeed, overexpressing Sdc3 in osteoblasts using the Col1a1 promoter rescues the low bone volume phenotype of the Sdc3−/− mice, and also increases bone volume in WT mice. Mechanistically, SDC3 enhances canonical WNT signaling in osteoblasts through stabilization of Frizzled 1, making SDC3 an attractive target for novel bone anabolic drug development. |
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The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however, anabolic therapeutics are few and their use is time restricted. Here, we report that Syndecan‐3 increases new bone formation through enhancement of WNT signaling in osteoblasts. Young adult Sdc3−/− mice have low bone volume, reduced bone formation, increased bone marrow adipose tissue, increased bone fragility, and a blunted anabolic bone formation response to mechanical loading. This premature osteoporosis‐like phenotype of Sdc3−/− mice is due to delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast‐mediated bone resorption. Indeed, overexpressing Sdc3 in osteoblasts using the Col1a1 promoter rescues the low bone volume phenotype of the Sdc3−/− mice, and also increases bone volume in WT mice. Mechanistically, SDC3 enhances canonical WNT signaling in osteoblasts through stabilization of Frizzled 1, making SDC3 an attractive target for novel bone anabolic drug development.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.202002024R</identifier><identifier>PMID: 33769615</identifier><language>eng</language><publisher>United States: John Wiley and Sons Inc</publisher><subject>Animals ; Animals, Newborn ; Antibodies ; bone ; Bone Development - physiology ; Cell Proliferation ; Fetal Development ; frizzled ; Male ; Mice ; Mice, Knockout ; osteoblast ; Osteoblasts ; Osteoclasts ; Syndecan-3 - genetics ; Syndecan-3 - metabolism ; Syndecan‐3 ; WNT ; Wnt Signaling Pathway - physiology</subject><ispartof>The FASEB journal, 2021-04, Vol.35 (4), p.e21246-n/a</ispartof><rights>2020 The Authors. published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.</rights><rights>2020 The Authors. 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Mechanistically, SDC3 enhances canonical WNT signaling in osteoblasts through stabilization of Frizzled 1, making SDC3 an attractive target for novel bone anabolic drug development.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Antibodies</subject><subject>bone</subject><subject>Bone Development - physiology</subject><subject>Cell Proliferation</subject><subject>Fetal Development</subject><subject>frizzled</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>osteoblast</subject><subject>Osteoblasts</subject><subject>Osteoclasts</subject><subject>Syndecan-3 - genetics</subject><subject>Syndecan-3 - metabolism</subject><subject>Syndecan‐3</subject><subject>WNT</subject><subject>Wnt Signaling Pathway - physiology</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAQhq0KRJeWY68oRy4p47E9SS5IZdUCUgUSLeJoOc5k16usXeLdor3xCDwjT0KqLS1ckEaaw3z65tcvxImEUwkNve5XpwgI06D-fCBm0igoqSZ4ImZQN1gSqfpQPM95BQASJD0Th0pV1JA0MzG_2sWOvYu_fvxUBceli55z4aJr0xB80abIRZ_GtduEFIvNckzbxbL4-vG6yGER3RDi4lg87d2Q-cX9PhJfLs6v5-_Ly0_vPszPLkuvFVJZA7eAqCUbYHLIuieSrTcNUU-aTKsYja46Ddh0VWu062ok56ekCpDVkXiz995s2zV3nuNmdIO9GcPajTubXLD_XmJY2kW6tTUaSVhPglf3gjF923Le2HXInofBRU7bbNEAYVUZ0BNa7lE_ppxH7h_eSLB3xdt-ZR-Ln_iXf2d7oP80PQF6D3wPA-_-b7MXV28RJWpSvwF8z451</recordid><startdate>202104</startdate><enddate>202104</enddate><creator>Johnson de Sousa Brito, Francesca Manuela</creator><creator>Butcher, Andrew</creator><creator>Pisconti, Addolorata</creator><creator>Poulet, Blandine</creator><creator>Prior, Amanda</creator><creator>Charlesworth, Gemma</creator><creator>Sperinck, Catherine</creator><creator>Scotto di Mase, Michele</creator><creator>Liu, Ke</creator><creator>Bou‐Gharios, George</creator><creator>Jurgen van 't Hof, Robert</creator><creator>Daroszewska, Anna</creator><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8193-6788</orcidid><orcidid>https://orcid.org/0000-0002-9631-8720</orcidid><orcidid>https://orcid.org/0000-0002-9563-9418</orcidid><orcidid>https://orcid.org/0000-0002-6692-6610</orcidid><orcidid>https://orcid.org/0000-0001-9376-0487</orcidid></search><sort><creationdate>202104</creationdate><title>Syndecan‐3 enhances anabolic bone formation through WNT signaling</title><author>Johnson de Sousa Brito, Francesca Manuela ; Butcher, Andrew ; Pisconti, Addolorata ; Poulet, Blandine ; Prior, Amanda ; Charlesworth, Gemma ; Sperinck, Catherine ; Scotto di Mase, Michele ; Liu, Ke ; Bou‐Gharios, George ; Jurgen van 't Hof, Robert ; Daroszewska, Anna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4326-80eb02241e50e6a2e4f661bc5966f6465b3e2547d4029d7b54ad826ac961302e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Antibodies</topic><topic>bone</topic><topic>Bone Development - physiology</topic><topic>Cell Proliferation</topic><topic>Fetal Development</topic><topic>frizzled</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>osteoblast</topic><topic>Osteoblasts</topic><topic>Osteoclasts</topic><topic>Syndecan-3 - genetics</topic><topic>Syndecan-3 - metabolism</topic><topic>Syndecan‐3</topic><topic>WNT</topic><topic>Wnt Signaling Pathway - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johnson de Sousa Brito, Francesca Manuela</creatorcontrib><creatorcontrib>Butcher, Andrew</creatorcontrib><creatorcontrib>Pisconti, Addolorata</creatorcontrib><creatorcontrib>Poulet, Blandine</creatorcontrib><creatorcontrib>Prior, Amanda</creatorcontrib><creatorcontrib>Charlesworth, Gemma</creatorcontrib><creatorcontrib>Sperinck, Catherine</creatorcontrib><creatorcontrib>Scotto di Mase, Michele</creatorcontrib><creatorcontrib>Liu, Ke</creatorcontrib><creatorcontrib>Bou‐Gharios, George</creatorcontrib><creatorcontrib>Jurgen van 't Hof, Robert</creatorcontrib><creatorcontrib>Daroszewska, Anna</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johnson de Sousa Brito, Francesca Manuela</au><au>Butcher, Andrew</au><au>Pisconti, Addolorata</au><au>Poulet, Blandine</au><au>Prior, Amanda</au><au>Charlesworth, Gemma</au><au>Sperinck, Catherine</au><au>Scotto di Mase, Michele</au><au>Liu, Ke</au><au>Bou‐Gharios, George</au><au>Jurgen van 't Hof, Robert</au><au>Daroszewska, Anna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Syndecan‐3 enhances anabolic bone formation through WNT signaling</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2021-04</date><risdate>2021</risdate><volume>35</volume><issue>4</issue><spage>e21246</spage><epage>n/a</epage><pages>e21246-n/a</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>Osteoporosis is the most common age‐related metabolic bone disorder, which is characterized by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. 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subjects | Animals Animals, Newborn Antibodies bone Bone Development - physiology Cell Proliferation Fetal Development frizzled Male Mice Mice, Knockout osteoblast Osteoblasts Osteoclasts Syndecan-3 - genetics Syndecan-3 - metabolism Syndecan‐3 WNT Wnt Signaling Pathway - physiology |
title | Syndecan‐3 enhances anabolic bone formation through WNT signaling |
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