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<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="LEVyLyKRyZURUvnMfAuRy6bg6sHDaHYV2rFDoodd8AHlOWtCST7T2eHUEwpP3iwf">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="LEVyLyKRyZURUvnMfAuRy6bg6sHDaHYV2rFDoodd8AHlOWtCST7T2eHUEwpP3iwf">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="LEVyLyKRyZURUvnMfAuRy6bg6sHDaHYV2rFDoodd8AHlOWtCST7T2eHUEwpP3iwf">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="LEVyLyKRyZURUvnMfAuRy6bg6sHDaHYV2rFDoodd8AHlOWtCST7T2eHUEwpP3iwf">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="LEVyLyKRyZURUvnMfAuRy6bg6sHDaHYV2rFDoodd8AHlOWtCST7T2eHUEwpP3iwf">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="23200862">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(12)00537-X"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3048&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=23200862&amp;db=pubmed&amp;nlmid=0370475"
title="See full text options at Elsevier Science"
data-ga-category="full_text"
data-ga-action="Elsevier Science"
data-ga-label="23200862"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-celloa.png" alt="Elsevier Science full text link"><span class="text">
Elsevier Science
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/23200862/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=23200862&amp;db=pubmed&amp;nlmid=0370475"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="23200862"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/23200862/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/23200862/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="23200862" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F23200862%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="LEVyLyKRyZURUvnMfAuRy6bg6sHDaHYV2rFDoodd8AHlOWtCST7T2eHUEwpP3iwf"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
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><sup class="key">1</sup> BioMarin Pharmaceutical, Novato, CA 94949, USA.</li>
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Achondroplasia (ACH), the most common form of dwarfism, is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). Here, we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia.
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Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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<img class="figure-thumb" itemprop="thumbnail"
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<strong class="figure-label">
<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><p> ACH-Related Clinical Features in <i> Fgfr3… </i> </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><p> ACH-Related Clinical Features in <i> Fgfr3 </i> <sup> <i> Y367C/+ </i> </sup> Mice (A) <i> Fgfr3 </i> <sup> <i> Y367C/+ </i> </sup> mice exhibit a… </p></div>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1
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<div class="figure-caption-contents">ACH-Related Clinical Features in <i>Fgfr3</i><sup><i>Y367C/+</i></sup> Mice (A) <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice exhibit a severe dwarfism phenotype. Mice presented are littermates and are 17 days old. (B) Computed-tomography (CT) scans of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> (n = 5) and <i>Fgfr3</i><sup><i>+/+</i></sup> mice (n = 5) (top) and ACH and control human skulls (15 years of age) (bottom) show a domed skull (arrow) with an anterior crossbite (arrow) in <i>Fgfr3</i> mutants. CT scans were performed with a VivaCT40 microscanner (SCANCO Medical, Laboratoire de Biologie Intégrative du Tissu Osseux, Institut National de la Santé et de la Recherche Médicale Unité U1059) according to the following protocols: 0.020 mm voxel resolution, 55 kV, sigma 1.5, support 2, threshold 148, and 150 uA. (C) MRI analysis of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> (n = 4) and <i>Fgfr3</i><sup><i>+/+</i></sup> mice (n = 4) (3 weeks of age) (top) and ACH and control humans (16 years of age) (bottom) shows medullary and upper-spinal-cord compression (arrow) in a pathological case. After three averages, a repetition time of 1,200 ms (echo time 80 ms), and two dummy scans, the resolution in mice was 0.0078 cm/px × 0.0078 cm/px × 625 micron/px for a matrix size of 256 × 256 × 32. The total scan time was 30 min. In humans, MRI was performed with a 1.5 tesla (Signa General Electric Medical Systems, Milwaukee, WI, USA) scanner with the following sequences: FSE T2 (TR/TE: 5,000/108, 3 mm slices, 0.3 mm gap). MRI was performed without intravenous contrast enhancement. Osirix software was used for postprocessing. (D) Hematoxylin and eosin (H&E) staining of the growth plate of 2-week-old <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (n = 20) shows a decrease in the height of the hypertrophic (HZ) zone. The area of the <i>Fgfr3</i><sup><i>Y367C/+</i></sup> hypertrophic cells is smaller than that of <i>Fgfr3</i><sup><i>+/+</i></sup> cells (arrows). H&amp;E analysis of the growth plate from a TD (c.1118A&gt;G [p.Tyr373Cys] mutation) fetus (16 weeks of age), from an ACH (c.1138G&gt;A [p.Gly380Arg] mutation) fetus, and from a control fetus (25 weeks of age) shows a gradient of extremely severe (TD) to moderate (ACH) (arrows) defects in the growth-plate architecture. The size of the hypertrophic cells from the ACH growth plate is smaller than that of the control cells. Comparative analyses of human and mouse growth plates shows that the cartilage of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (n = 30) resembles that of ACH mice (n = 15) more than that of TD mice (n = 25). The scale bars represent 50 μm.</div>
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<img class="figure-thumb" itemprop="thumbnail"
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<strong class="figure-label">
<p> Figure 2 </p>
</strong>
<div class="figure-caption-contents"><p> BMN 111 Reduced ERK1/2 Activation… </p></div>
</div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2 </p>
</strong>
<div class="figure-caption-contents"><p> BMN 111 Reduced ERK1/2 Activation in ACH Growth-Plate Chondrocytes (A) Control and pathologic… </p></div>
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<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2
</strong>
<div class="figure-caption-contents">BMN 111 Reduced ERK1/2 Activation in ACH Growth-Plate Chondrocytes (A) Control and pathologic human chondrocytes (ACH) were isolated as described previously and treated with BMN 111 (10<sup>5</sup> M) prior to coincubation with fibroblast growth factor (FGF) (100 ng/ml FGF18). BMN 111 pretreatment partially prevented FGF-mediated increase in ERK1/2 phosphorylation (n = 6). The cell lysates were subjected to SDS polyacrylamide-gel electrophoresis and were hybridized overnight at 4°C with phosphorylated-ERK1/2 antibody (1/1,000) (Cell Signaling Technology, Danvers, MA, USA) or ERK1/2 antibody (1/1,000) (Cell Signaling Technology). A secondary antibody coupled to peroxidase was used at a dilution of 1:10,000 (GE Healthcare Life Sciences, Pittsburgh, PA, USA). Bound proteins were detected by enhanced chemiluminescence (GE Healthcare Life Sciences). (B) Immunoblot showing STAT3-P and STAT3 (dilution 1:1,000, Cell Signaling Technology) in human ACH growth-plate chondrocytes (n = 3). The phosphorylation of STAT3 did not appear decreased upon BMN 111 coincubation.</div>
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
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<strong class="figure-label">
<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> CNP Analog Improved the Size… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> CNP Analog Improved the Size and Growth-Plate Defect in an Ex Vivo <i> Fgfr3… </i> </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 3
</strong>
<div class="figure-caption-contents">CNP Analog Improved the Size and Growth-Plate Defect in an Ex Vivo <i>Fgfr3</i><sup><i>Y367C/+</i></sup> Mouse Model (A) FGFR3 and NPR-B localization in the proliferative (PZ) and prehypertrophic (PHZ) zones of the cartilage. Serial histology sections of the growth plate from <i>Fgfr3</i><sup><i>+/+</i></sup> and <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (n = 6) were stained by immunochemistry with an FGFR3 antibody (1:250 dilution; Sigma-Aldrich, St. Louis, MO, USA) and an NPR-B antibody (1:100 dilution; Abcam [ab14357-ICC/IF/WB], Cambridge, UK) and were visualized with the Dako Envision kit with an anti-rabbit antibody (secondary antibody) (Dako North America, Carpinteria, CA, USA). Images were captured with an Olympus PD70-IX2-UCB microscope (Olympus, Tokyo, Japan). (B) A partial normalization of the growth defect, as well as enlargement of the epiphysis, was observed in the BMN-111-coincubated femurs (n = 25) isolated from <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mouse embryos (E16.5) after 6 days of culture in Dulbecco's modified Eagle's medium with antibiotics and 0.2% bovine serum albumin (Sigma-Aldrich) supplemented with BMN 111 (BMN 111 patent US2010-0297021, BioMarin Pharmaceutical, Novato, CA, USA). (C) Quantitative gain in femur length after coincubation with BMN 111 (10<sup>6</sup> M to 10<sup>10</sup> M) or vehicle. A partial concentration-dependent restoration of the growth-plate defect was observed in <i>Fgfr3</i><sup><i>Y367C/+</i></sup> femurs coincubated with BMN 111 (BMN 111 10<sup>6</sup> M, n = 13; 10<sup>7</sup> M, n = 10; 10<sup>8</sup> M, n = 8; 10<sup>9</sup> M, n = 6; and 10<sup>10</sup> M, n = 6). <sup></sup>p &lt; 0.05, <sup></sup>p &lt; 0.001, Student's t test. Error bars indicate the SD. (D) H&E staining of longitudinal sections of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> (n = 11) and <i>Fgfr3</i><sup><i>+/+</i></sup> (n = 16) femurs coincubated with BMN 111 (10<sup>6</sup> M) or vehicle. An increase in the height of the proliferative and hypertrophic zones of the growth plate, along with the normalization of the shape of the chondrocytes, was observed in BMN-111<i>-</i>treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> femurs. The enlarged regions are boxed. The scale bar in the “Proximal femur” row represents 200 μm, the scale bar in the “Growth plate” row represents 100 μm, and the scale bar in the “Hypertrophic zone” row represents 20 μm. (E) Type-X-collagen (1:30 dilution, Quartett, Berlin, Germany) immunohistochemical staining of the hypertrophic zone of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> femurs coincubated with BMN 111 (10<sup>6</sup> M) or vehicle. A partial restoration of the size of the hypertrophic zone was observed in BMN-111-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> femurs (n = 11) compared to vehicle-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> femurs coincubated with vehicle (n = 11). The scale bar represents 100 μm.</div>
</figcaption>
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
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<p> Figure 4 </p>
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<div class="figure-caption-contents"><p> CNP Analog Partially Corrected the… </p></div>
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<p> Figure 4 </p>
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<div class="figure-caption-contents"><p> CNP Analog Partially Corrected the Dwarfism of <i> Fgfr3 </i> <sup> <i> Y367C/+ </i> </sup> Mice (A) Phenotypic changes… </p></div>
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Figure 4
</strong>
<div class="figure-caption-contents">CNP Analog Partially Corrected the Dwarfism of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> Mice (A) Phenotypic changes were observed in 800 μg/kg BMN-111-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (n = 9) compared to vehicle-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (n = 9) and included flattening of the skull and an increased length of the long bones and tail. <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice received once-daily SC administrations of BMN 111 or vehicle (0.03 mol/l acetic acid buffer solution, pH 4.0, containing 1% [w/v] benzyl alcohol and 10% [w/v] sucrose) for 10 days. All mice were dosed approximately 2 hr prior to the dark cycle. (B) Histological safranin-O (top) or H&E staining of growth plates from <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice treated or not with 240 μg/kg or 800 μg/kg BMN 111 during 10 days. Dose-dependent modifications of the epiphysis were observed in distal-femur sections of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice. The formation of the secondary ossification center was delayed in vehicle-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice compared to vehicle-treated <i>Fgfr3</i><sup><i>+/+</i></sup>mice (arrow). CNP analog treatment (800 μg/kg) did not appear to accelerate the ossification process. The scale bars in the “Cartilage” and “Distal epiphysis” rows represent 200 μm, the scale bars in the “Growth plate” row represent 50 μm, and the scale bars in the “Hypertrophic zone” row represent 20 μm. (C) Pictures of <i>Fgfr3</i><sup><i>+/+</i></sup> (n = 5) and <i>Fgfr3</i><sup><i>Y367C/+</i></sup> (n = 5) mice treated during 20 days with 800 μg/kg BMN 111. Phenotypic changes comprise evident lengthening and straightening of the limbs, as well as longer forelimbs and hind limbs, including paws and digits, in BMN-111-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup>mice (n = 5). (D) X-rays of the skeleton show flattening of the skull (arrow) and improvement in the snout (arrow) in BMN-111-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice. X-rays of the hind limbs show straightening of both the tibia and femur in BMN-111-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (arrows) and a marked increased in the size of the digits (arrows). (E) Histological analysis of the distal femur of <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice with or without BMN 111 treatment after 20 days. Rescue of the height and architecture of the different zones of the growth plate, along with replicating and hypertrophic chondrocytes organized in columns, was observed in BMN-111-treated <i>Fgfr3</i><sup><i>Y367C/+</i></sup>mice. The shape and size of the proliferative zone, visualized by type-II-collagen (Col II) in-situ-hybridization labeling (type-II-collagen riboprobe<sup>21</sup>) and KI67 immunolabeling (KI67 antibody, 1:3,000 dilution, Abcam), were modified after 800 μg/kg BMN 111 treatment in <i>Fgfr3</i><sup><i>Y367C/+</i></sup> mice (arrows). The scale bar in the “Distal epiphysis” row represents 200 μm, and the scale bars in the “Growth plate,” “Col II,” and “KI67” rows represent 50 μm.</div>
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