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Muc5b-deficient mice develop early histological lung abnormalities.

ABSTRACT: Gel-forming mucins are the main organic component responsible for physical properties of the mucus hydrogels. While numerous biological functions of these mucins are well documented, specific physiological functions of each mucin are largely unknown. To investigate in vivo functions of the gel-forming mucin Muc5b, which is one of the major secreted airway mucins, along with Muc5ac, we generated mice in which Muc5b was disrupted and maintained in the absence of environmental stress. Adult Muc5b-deficient mice displayed bronchial hyperplasia and metaplasia, interstitial thickening, alveolar collapse, immune cell infiltrates, fragmented and disorganized elastin fibers and collagen deposits that were, for approximately one-fifth of the mice, associated with altered pulmonary function leading to respiratory failure. These lung abnormalities start early in life, as demonstrated in one-quarter of 2-day-old Muc5b-deficient pups. Thus, the mouse mucin Muc5b is essential for maintaining normal lung function.

SUBMITTER: Valque H

PROVIDER: S-EPMC6899002 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Muc5b-deficient mice develop early histological lung abnormalities.

Valque Hélène H Gouyer Valérie V Duez Catherine C Leboeuf Christophe C Marquillies Philippe P Le Bert Marc M Plet Ségolène S Ryffel Bernhard B Janin Anne A Gottrand Frédéric F Desseyn Jean-Luc JL

Biology open 20191107 11

Gel-forming mucins are the main organic component responsible for physical properties of the mucus hydrogels. While numerous biological functions of these mucins are well documented, specific physiological functions of each mucin are largely unknown. To investigate <i>in vivo</i> functions of the gel-forming mucin Muc5b, which is one of the major secreted airway mucins, along with Muc5ac, we generated mice in which Muc5b was disrupted and maintained in the absence of environmental stress. Adult ...[more]

PMID: 31699684

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Project description:Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss, osteoarthritis and HME.

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Muc5b-deficient mice develop early histological lung abnormalities.

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Muc5b-deficient mice develop early histological lung abnormalities.

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