title: Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice.
abstract: 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.
authors: Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Federica
authors: F
authors: Sgariglia
authors: Maria Elena
authors: ME
authors: Candela
authors: Julianne
authors: J
authors: Huegel
authors: Olena
authors: O
authors: Jacenko
authors: Eiki
authors: E
authors: Koyama
authors: Yu
authors: Y
authors: Yamaguchi
authors: Maurizio
authors: M
authors: Pacifici
authors: Motomi
authors: M
authors: Enomoto-Iwamoto
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D006132:Growth Plate; D015576:Hyperostosis / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency* / Q000235:genetics; D000099058:Exostosin 1
chemical_list: D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1
keywords: Articular cartilage; BMP; Ext1; FGF; Growth plate; HME; HS; HSPGs; Heparan sulfate; Hereditary Multiple Exostoses; Ihh; Indian hedgehog; Long bones; MMP-13; TRAP; VEGFs; bone morphogenetic protein; fibroblast growth factor; heparan sulfate; heparan sulfate proteoglycans; matrix metalloprotease 13; tartrate-resistant acid phosphatase; vascular endothelial growth factors
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