Differential Effects of Collagen Prolyl 3-Hydroxylation on Skeletal Tissues
Publication Date
January 23, 2014
Journal
PLOS Genetics
Authors
Erica P. Homan, Caressa Lietman, Ingo Grafe, Jennifer Lennington, et al
Volume
10
Issue
1
Pages
e1004121
DOI
https://dx.plos.org/10.1371/journal.pgen.1004121
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1004121
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24465224
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900401
Europe PMC
http://europepmc.org/abstract/MED/24465224
Web of Science
000336525000067
Scopus
84893787353
Mendeley
http://www.mendeley.com/research/differential-effects-collagen-prolyl-3hydroxylation-skeletal-tissues
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Mendeley | Further Information

{"title"=>"Differential Effects of Collagen Prolyl 3-Hydroxylation on Skeletal Tissues", "type"=>"journal", "authors"=>[{"first_name"=>"Erica P.", "last_name"=>"Homan", "scopus_author_id"=>"36458320800"}, {"first_name"=>"Caressa", "last_name"=>"Lietman", "scopus_author_id"=>"54403394900"}, {"first_name"=>"Ingo", "last_name"=>"Grafe", "scopus_author_id"=>"6506124037"}, {"first_name"=>"Jennifer", "last_name"=>"Lennington", "scopus_author_id"=>"6507184221"}, {"first_name"=>"Roy", "last_name"=>"Morello", "scopus_author_id"=>"7003564196"}, {"first_name"=>"Dobrawa", "last_name"=>"Napierala", "scopus_author_id"=>"6603373632"}, {"first_name"=>"Ming Ming", "last_name"=>"Jiang", "scopus_author_id"=>"7401861474"}, {"first_name"=>"Elda M.", "last_name"=>"Munivez", "scopus_author_id"=>"14829467100"}, {"first_name"=>"Brian", "last_name"=>"Dawson", "scopus_author_id"=>"7103387135"}, {"first_name"=>"Terry K.", "last_name"=>"Bertin", "scopus_author_id"=>"36866804600"}, {"first_name"=>"Yuqing", "last_name"=>"Chen", "scopus_author_id"=>"56032555400"}, {"first_name"=>"Rhonald", "last_name"=>"Lua", "scopus_author_id"=>"6507847837"}, {"first_name"=>"Olivier", "last_name"=>"Lichtarge", "scopus_author_id"=>"7003903180"}, {"first_name"=>"John", "last_name"=>"Hicks", "scopus_author_id"=>"7202879583"}, {"first_name"=>"Mary Ann", "last_name"=>"Weis", "scopus_author_id"=>"7007054740"}, {"first_name"=>"David", "last_name"=>"Eyre", "scopus_author_id"=>"7102483998"}, {"first_name"=>"Brendan H.L.", "last_name"=>"Lee", "scopus_author_id"=>"8756068700"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "pui"=>"372348837", "doi"=>"10.1371/journal.pgen.1004121", "sgr"=>"84893787353", "scopus"=>"2-s2.0-84893787353", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"24465224"}, "id"=>"80b134b0-7a34-3e49-b852-4700f6929df4", "abstract"=>"Mutations in the genes encoding cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1 encoded by LEPRE1) were the first identified causes of recessive Osteogenesis Imperfecta (OI). These proteins, together with cyclophilin B (encoded by PPIB), form a complex that 3-hydroxylates a single proline residue on the α1(I) chain (Pro986) and has cis/trans isomerase (PPIase) activity essential for proper collagen folding. Recent data suggest that prolyl 3-hydroxylation of Pro986 is not required for the structural stability of collagen; however, the absence of this post-translational modification may disrupt protein-protein interactions integral for proper collagen folding and lead to collagen over-modification. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other. Hence, hypomorphic or loss of function mutations of either gene cause loss of the whole complex and its associated functions. The relative contribution of losing this complex's 3-hydroxylation versus PPIase and collagen chaperone activities to the phenotype of recessive OI is unknown. To distinguish between these functions, we generated knock-in mice carrying a single amino acid substitution in the catalytic site of P3h1 (Lepre1(H662A) ). This substitution abolished P3h1 activity but retained ability to form a complex with Crtap and thus the collagen chaperone function. Knock-in mice showed absence of prolyl 3-hydroxylation at Pro986 of the α1(I) and α1(II) collagen chains but no significant over-modification at other collagen residues. They were normal in appearance, had no growth defects and normal cartilage growth plate histology but showed decreased trabecular bone mass. This new mouse model recapitulates elements of the bone phenotype of OI but not the cartilage and growth phenotypes caused by loss of the prolyl 3-hydroxylation complex. Our observations suggest differential tissue consequences due to selective inactivation of P3H1 hydroxylase activity versus complete ablation of the prolyl 3-hydroxylation complex.", "link"=>"http://www.mendeley.com/research/differential-effects-collagen-prolyl-3hydroxylation-skeletal-tissues", "reader_count"=>23, "reader_count_by_academic_status"=>{"Librarian"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>1, "Professor > Associate Professor"=>1, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Librarian"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>1, "Professor > Associate Professor"=>1, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Materials Science"=>1, "Medicine and Dentistry"=>9, "Agricultural and Biological Sciences"=>7, "Sports and Recreations"=>1, "Immunology and Microbiology"=>1, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>2, "United Kingdom"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1358816"], "description"=>"<p>Hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), were measured in bone collagen. Listed are the HP and LP contents (moles/mole of collagen), and the molar ratio (HP/LP) for <i>Lepre1<sup>H662A/H662A</sup></i> and <i>Lepre1<sup>+/+</sup></i> mice showing a significant increase in the HP/LP ratio in the <i>Lepre1<sup>H662A/H662A</sup></i> mice consistent with more hydroxylated lysines at helical cross-linking sites (N = 5, p<0.02). The percentage hydroxylation of α1(I) chain N- and C- telopeptides from mass spectrometry appeared not to be affected (N = 1, both genotypes, p = NS).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "telopeptide", "hydroxylation"], "article_id"=>910944, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.t002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pyridinoline_content_and_telopeptide_hydroxylation_of_bone_collagen_/910944", "title"=>"Pyridinoline content and telopeptide hydroxylation of bone collagen.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358814"], "description"=>"<p>Analysis of procollagen secretion by the collagen pulse-chase assay suggests that the procollagen secreted from <i>Lepre1<sup>H662A/H662A</sup></i> fibroblasts is similar to <i>Lepre1<sup>+/+</sup></i> fibroblasts (A, B). Additionally, there does not appear to be a decrease in the amount of procollagen secreted from the <i>Lepre1<sup>H662A/H662A</sup></i> fibroblasts in comparison to <i>Lepre1<sup>+/+</sup></i> fibroblasts (A, B). These findings are in contrast to that of the <i>Crtap<sup>−/−</sup></i> fibroblasts, which have an increase in the rate of procollagen secretion (A). Collagen modification was assessed using the collagen steady-state assay. We observed no difference in the migration pattern of procollagen and collagen isolated from <i>Lepre1<sup>+/+</sup></i>(+/+) and <i>Lepre1<sup>H662A/H662A</sup></i> (H662A/H662A) fibroblasts (C). These assays were repeated three times.</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "fibroblast", "procollagen", "secretion", "collagen", "modification"], "article_id"=>910942, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g009", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lepre1_H662A_H662A_fibroblast_procollagen_secretion_rate_and_collagen_modification_is_normal_/910942", "title"=>"<i>Lepre1<sup>H662A/H662A</sup></i> fibroblast procollagen secretion rate and collagen modification is normal.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358828", "https://ndownloader.figshare.com/files/1358829"], "description"=>"<div><p>Mutations in the genes encoding cartilage associated protein (<i>CRTAP</i>) and prolyl 3-hydroxylase 1 (P3H1 encoded by <i>LEPRE1</i>) were the first identified causes of recessive Osteogenesis Imperfecta (OI). These proteins, together with cyclophilin B (encoded by <i>PPIB</i>), form a complex that 3-hydroxylates a single proline residue on the α1(I) chain (Pro986) and has cis/trans isomerase (PPIase) activity essential for proper collagen folding. Recent data suggest that prolyl 3-hydroxylation of Pro986 is not required for the structural stability of collagen; however, the absence of this post-translational modification may disrupt protein-protein interactions integral for proper collagen folding and lead to collagen over-modification. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other. Hence, hypomorphic or loss of function mutations of either gene cause loss of the whole complex and its associated functions. The relative contribution of losing this complex's 3-hydroxylation versus PPIase and collagen chaperone activities to the phenotype of recessive OI is unknown. To distinguish between these functions, we generated knock-in mice carrying a single amino acid substitution in the catalytic site of P3h1 (<i>Lepre1<sup>H662A</sup></i>). This substitution abolished P3h1 activity but retained ability to form a complex with Crtap and thus the collagen chaperone function. Knock-in mice showed absence of prolyl 3-hydroxylation at Pro986 of the α1(I) and α1(II) collagen chains but no significant over-modification at other collagen residues. They were normal in appearance, had no growth defects and normal cartilage growth plate histology but showed decreased trabecular bone mass. This new mouse model recapitulates elements of the bone phenotype of OI but not the cartilage and growth phenotypes caused by loss of the prolyl 3-hydroxylation complex. Our observations suggest differential tissue consequences due to selective inactivation of P3H1 hydroxylase activity versus complete ablation of the prolyl 3-hydroxylation complex.</p></div>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "collagen", "prolyl", "3-hydroxylation", "skeletal"], "article_id"=>910956, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004121.s001", "https://dx.doi.org/10.1371/journal.pgen.1004121.s002"], "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_Effects_of_Collagen_Prolyl_3_Hydroxylation_on_Skeletal_Tissues_/910956", "title"=>"Differential Effects of Collagen Prolyl 3-Hydroxylation on Skeletal Tissues", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358810"], "description"=>"<p>By histomorphometry, we were able to confirm the low trabecular bone mass phenotype in the <i>Lepre1<sup>H662A/H662A</sup></i> mice as quantified by decreased bone volume (BV/TV) and trabecular thickness (Tb.Th). We observed no differences in osteoblast and osteoclast parameters, as measured by the number of osteoblasts (N.Ob/BS) and osteoclast surface (OcS/BS). We observed no difference in the kinetic indices of bone formation, as measured by mineral apposition (MAR), mineralizing surface (MS/BS) and bone formation rate (BFR/TV) and in osteoid parameters, as measured by osteoid volume (OV/BV) and osteoid surface (OS/BS) (mean ± SD, N = 9, both genotypes).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics"], "article_id"=>910938, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g007", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histomorphometry_of_Lepre1_H662A_H662A_mice_/910938", "title"=>"Histomorphometry of <i>Lepre1<sup>H662A/H662A</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358801"], "description"=>"<p>Mass spectral analysis of Pro986 hydroxylation in tryptic peptides from the α2(V) chain of bone from <i>Lepre1<sup>+/+</sup></i> and <i>Lepre1<sup>H662A/H662A</sup></i> mice (A and B respectively) shows a marked reduction in hydroxylation at this site. The MS/MS fragmentation patterns shown in C and D identified the 765.8<sup>2+</sup> peptide and its 3-hydroxylated version 773.9<sup>2+</sup>. A portion (40%) of the latter ion was also found by MS/MS to be contributed by a version lacking 3-Hyp but containing 4-Hyp at P978 (taken into account in the 3-Hyp quantitation).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "3-hydroxylation", "pro986", "collagen"], "article_id"=>910929, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g003", "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Prolyl_3_hydroxylation_at_Pro986_in_the_945_2_V_collagen_chain_/910929", "title"=>"Prolyl 3-hydroxylation at Pro986 in the α2(V) collagen chain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358799"], "description"=>"<p>Upon generation of the <i>Lepre1<sup>H662A/H662A</sup></i> mice, we confirmed the stability of both P3H1 and CRTAP by western blot using protein isolated from mouse calvaria (A, experiments repeated 3 times). Comparing protein isolated from the <i>Lepre1<sup>H662A/H662A</sup></i> and the <i>Lepre1<sup>+/+</sup></i> mice, we found no differences in the levels of P3H1 and CRTAP when compared to γ-Tubulin. Analysis of prolyl 3-hydroxylation of Pro986 on the α(1) chain of type I collagen in bone using mass spectrometry demonstrates complete loss of 3-hydroxylation in the <i>Lepre1<sup>H662A/H662A</sup></i> mice when compared to <i>Lepre1<sup>+/+</sup></i> littermates (B). Similarly, analysis of the Pro986 site on the α1 chain of type II collagen in cartilage demonstrates a reduction to 9% 3-hydroxylation in the <i>Lepre1<sup>H662A/H662A</sup></i> mice and is similar to what was reported in <i>Crtap<sup>−/−</sup></i> mice (C).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "prolyl", "3-hydroxylation", "pro986", "collagen", "ii"], "article_id"=>910927, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_Prolyl_3_hydroxylation_at_Pro986_in_type_I_collagen_in_bone_and_type_II_collagen_in_cartilage_/910927", "title"=>"Loss of Prolyl 3-hydroxylation at Pro986 in type I collagen in bone and type II collagen in cartilage.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358798"], "description"=>"<p>Evolutionary trace analysis identified residues important for the function of P3H1 by comparing each residue within the dioxygenase domain family. The highest ranking residues are mapped onto the dioxygenase domain responsible for prolyl 3-hydroxylation (A). These residues include 3 that interact with iron (His590, Asp592, and His662) shown in red and 1 that interacts with 2-oxoglutarate (Arg672) shown in yellow. An alanine substitution was introduced at HIS662 (H662A) to deactivate the hydroxylase function. To test whether the mutant P3H1 was able to rescue the stability of CRTAP, we transduced immortalized <i>LEPRE1</i> loss of function fibroblasts with WT or H662A mutant <i>LEPRE1</i> cDNA and assayed for the presence of CRTAP by immunofluorescence and immunoblot. Here we demonstrate that the stability of CRTAP is rescued by immunofluorescence (B) and by immunoblot (C).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "hydroxylase", "catalytic", "mutations"], "article_id"=>910926, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Residues_important_for_hydroxylase_function_and_catalytic_mutations_rescue_the_stability_of_CRTAP_/910926", "title"=>"Residues important for hydroxylase function and catalytic mutations rescue the stability of CRTAP.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358812"], "description"=>"<p>Transmission EM analysis of collagen fibrils from skin revealed fibrils more homogenous in size in the <i>Lepre1<sup>H662A/H662A</sup></i> mice as compared to the wild-type littermates. Additionally, the collagen fibril diameters are slightly smaller, as quantified by a slight increase in the proportion of smaller diameter collagen fibrils. (bar = 100 nm). (N = 3,150 collagen diameters measured per animal, p<0.05).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "mice", "smaller", "collagen", "fibril"], "article_id"=>910940, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g008", "stats"=>{"downloads"=>3, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lepre1_H662A_H662A_mice_have_smaller_collagen_fibril_diameter_/910940", "title"=>"<i>Lepre1<sup>H662A/H662A</sup></i> mice have smaller collagen fibril diameter.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358807"], "description"=>"<p>Since the <i>Lepre1<sup>−/−</sup></i> animals showed disorganization of the hypertrophic zone, we assessed the hypertrophic zone (P1) of <i>Lepre1<sup>H662A/H662A</sup></i> mice by H&E staining (A) and by specifically marking the hypertrophic zone using an antibody directed against type×collagen (B). The hypertrophic zone of the femur of the <i>Lepre1<sup>H662A/H662A</sup></i> mice are indistinguishable from their wild-type littermates (B) and this is confirmed by quantifying the width of the hypertrophic zone in which there is no difference in the width between genotypes (C) (N = 10, both genotypes).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "mice", "femoral", "hypertrophic"], "article_id"=>910935, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g005", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lepre1_H662A_H662A_mice_have_a_normal_femoral_hypertrophic_zone_/910935", "title"=>"<i>Lepre1<sup>H662A/H662A</sup></i> mice have a normal femoral hypertrophic zone.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358808"], "description"=>"<p>3D reconstruction of spines from the <i>Lepre1<sup>H662A/H662A</sup></i> mice compared to wild-type littermates. The <i>Lepre1<sup>H662A/H662A</sup></i> mice have less trabecular bone as quantified by reduced bone volume (BV/TV), reduced trabecular number (Tb.N), reduced trabecular thickness (Tb.Th), reduced trabecular bone mineral density (BMD), and increased trabecular separation (Tb.Sp). Cortical parameters are similar to wild-type, as quantified by normal cortical BMD or stiffness and force to failure. These results suggest that the <i>Lepre1<sup>H662A/H662A</sup></i> mice have normal cortical bone but reduced trabecular bone. (N = 10, each genotype).</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "tomography", "cortical", "biomechanical"], "article_id"=>910936, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g006", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Micro_Computed_Tomography_and_cortical_biomechanical_analyses_/910936", "title"=>"Micro-Computed Tomography and cortical biomechanical analyses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358803"], "description"=>"<p>Analysis at 3 months by X-ray shows no difference in terms of skeletal patterning between genotypes (A). By growth curve analysis, there is no difference in weight at any time point over 3 months between <i>Lepre1<sup>+/+</sup></i> and <i>Lepre1<sup>H662A/H662A</sup></i> mice (B). We assessed rhizomelia by measuring the length of both the femur and tibia and computing the ratio. Comparing <i>Lepre1<sup>+/+</sup></i> to <i>Lepre1<sup>H662A/H662A</sup></i> mice, we observed no difference in the length of the femur, tibia, or their ratio (C). N = 10, both genotypes.</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "mice"], "article_id"=>910931, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.g004", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lepre1_H662A_H662A_mice_are_normal_in_gross_morphology_/910931", "title"=>"<i>Lepre1<sup>H662A/H662A</sup></i> mice are normal in gross morphology.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358817"], "description"=>"<p>Table shows the percent 3-hydroxylation of proline at known sites of potential occupancy in type I and type II collagen of bone and cartilage determined by mass spectrometry.</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "collagen"], "article_id"=>910945, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.t001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hydroxylation_status_at_different_collagen_sites_/910945", "title"=>"Hydroxylation status at different collagen sites.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-23 04:18:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1358815"], "description"=>"<p>In contrast to the established KO mouse models, the <i>Lepre1<sup>H662A/H662A</sup></i> mice have a wild-type appearance, no delay in growth curve, and normal cortical bone. In addition, there is a slight decrease in collagen diameter.</p>", "links"=>[], "tags"=>["Evolutionary biology", "genetics", "comparing", "phenotype", "established", "oi"], "article_id"=>910943, "categories"=>["Biological Sciences"], "users"=>["Erica P. Homan", "Caressa Lietman", "Ingo Grafe", "Jennifer Lennington", "Roy Morello", "Dobrawa Napierala", "Ming-Ming Jiang", "Elda M. Munivez", "Brian Dawson", "Terry K. Bertin", "Yuqing Chen", "Rhonald Lua", "Olivier Lichtarge", "John Hicks", "Mary Ann Weis", "David Eyre", "Brendan H. L. Lee"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004121.t003", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Table_comparing_Lepre1_H662A_H662A_phenotype_to_established_OI_mouse_models_/910943", "title"=>"Table comparing <i>Lepre1<sup>H662A/H662A</sup></i> phenotype to established OI mouse models.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-23 04:18:33"}

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