title: ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice.
abstract: Long-bone growth by endochondral ossification is cooperatively accomplished by chondrocyte proliferation, hypertrophic differentiation, and appropriate secretion of collagens, glycoproteins, and proteoglycans into the extracellular matrix (ECM). Before folding and entering the secretory pathway, ECM macromolecules in general are subject to extensive posttranslational modification, orchestrated by chaperone complexes in the endoplasmic reticulum (ER). ERp57 is a member of the protein disulfide isomerase (PDI) family and facilitates correct folding of newly synthesized glycoproteins by rearrangement of native disulfide bonds. Here, we show that ERp57-dependent PDI activity is essential for postnatal skeletal growth, especially during the pubertal growth spurt characterized by intensive matrix deposition. Loss of ERp57 in growth plates of cartilage-specific ERp57 knockout mice (ERp57 KO) results in ER stress, unfolded protein response (UPR), reduced proliferation, and accelerated apoptotic cell death of chondrocytes. Together this results in a delay of long-bone growth with the following characteristics: (1) enlarged growth plates; (2) expanded hypertrophic zones; (3) retarded osteoclast recruitment; (4) delayed remodeling of the proteoglycan-rich matrix; and (5) reduced numbers of bone trabeculae. All the growth plate and bone abnormalities, however, become attenuated after the pubertal growth spurt, when protein synthesis is decelerated and, hence, ERp57 function is less essential.
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelms-University Münster, Münster, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Linz
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelms-University Münster, Münster, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Knieper
authors.affiliation: Institute of Experimental Musculoskeletal Medicine (IEMM), University Hospital Münster, Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gronau
authors.affiliation: Institute of Experimental Musculoskeletal Medicine (IEMM), University Hospital Münster, Münster, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hansen
authors.affiliation: Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Aszodi
authors.affiliation: Department of Molecular Immunology, Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.affiliation: Division of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.affiliation: Institute of Experimental Musculoskeletal Medicine (IEMM), University Hospital Münster, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelms-University Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bruckner
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Westfalian Wilhelms-University Münster, Münster, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Dreier
mesh_terms: D000818:Animals; D002356:Cartilage / Q000201:enzymology* / Q000473:pathology; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D006132:Growth Plate / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D012741:Sexual Maturation; D056811:Unfolded Protein Response
chemical_list: C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases
keywords: ENDOCHONDRAL OSSIFICATION; ER STRESS; ERP57; GROWTH PLATE; PUBERTY