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Procollagen C Proteinase Enhancer 1 Genes Are Important Determinants of the Mechanical Properties and Geometry of Bone and the Ultrastructure of Connective Tissues

Department of Pathology and Laboratory Medicine,¹ Waisman Center for Human Development and Developmental Disabilities Research, University of Wisconsin, Madison, Wisconsin 53706,⁵ Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109,² Center for Extracellular Matrix Biology, Albert B. Alkek Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030,³ Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107⁴

Received 12 August 2005/ Accepted 9 October 2005

Procollagen C proteinases (pCPs) cleave type I to III procollagen C propeptides as a necessary step in assembling the major fibrous components of vertebrate extracellular matrix. The protein PCOLCE1 (procollagen C proteinase enhancer 1) is not a proteinase but can enhance the activity of pCPs 10-fold in vitro and has reported roles in inhibiting other proteinases and in growth control. Here we have generated mice with null alleles of the PCOLCE1 gene, Pcolce, to ascertain in vivo roles. Although Pcolce^–/– mice are viable and fertile, Pcolce^–/– male, but not female, long bones are more massive and have altered geometries that increase resistance to loading, compared to wild type. Mechanical testing indicated inferior material properties of Pcolce^–/– male long bone, apparently compensated for by the adaptive changes in bone geometry. Male and female Pcolce^–/– vertebrae both appeared to compensate for inferior material properties with thickened and more numerous trabeculae and had a uniquely altered morphology in deposited mineral. Ultrastructurally, Pcolce^–/– mice had profoundly abnormal collagen fibrils in both mineralized and nonmineralized tissues. In Pcolce^–/– tendon, 100% of collagen fibrils had deranged morphologies, indicating marked functional effects in this tissue. Thus, PCOLCE1 is an important determinant of bone mechanical properties and geometry and of collagen fibril morphology in mammals, and the human PCOLCE1 gene is identified as a candidate for phenotypes with defects in such attributes in humans.

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