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TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions
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نویسنده
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zieba j. ,forlenza k.n. ,khatra j.s. ,sarukhanov a. ,duran i. ,rigueur d. ,lyons k.m. ,cohn d.h. ,merrill a.e. ,krakow d.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 3
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چکیده
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Spondylocarpotarsal synostosis (sct) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in filamin b (flnb). flnb acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems,yet the disease mechanisms for sct remain unclear. employing a flnb knockout mouse,we found morphologic and molecular evidence that the intervertebral discs (ivds) of flnb–/–mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the ivd,particularly the annulus fibrosus (af). in flnb–/–mice,the af cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. this change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix,expression of collagen x,increased apoptosis,and inappropriate ossification of the disc tissue. we show that conversion of the af cells into chondrocytes is coincident with upregulated tgfβ signaling via smad2/3 and bmp induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and ctgf. these findings indicate that flnb is involved in attenuation of tgfβ/bmp signaling and influences af cell fate. furthermore,we demonstrate that the ivd disruptions in flnb–/–mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. © 2016 zieba et al.
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آدرس
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department of human genetics,david geffen school of medicine at the university of california at los angeles,los angeles,ca,united states,department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca, United States, department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca, United States, department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca, United States, department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca, United States, department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca, United States, department of molecular,cell,and developmental biology,university of california at los angeles,los angeles,ca, United States, department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca,united states,department of molecular,cell,and developmental biology,university of california at los angeles,los angeles,ca, United States, department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca,united states,department of molecular,cell,and developmental biology,university of california at los angeles,los angeles,ca, United States, center for craniofacial molecular biology,ostrow school of dentistry,university of southern california,los angeles,ca,united states,department of biochemistry and molecular biology,keck school of medicine,university of southern california,los angeles,ca, United States, department of human genetics,david geffen school of medicine at the university of california at los angeles,los angeles,ca,united states,department of orthopaedic surgery,david geffen school of medicine at the university of california at los angeles,los angeles,ca,united states,department of obstetrics and gynecology,david geffen school of medicine at the university of california at los angeles,los angeles,ca, United States
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Authors
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