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Site-1 protease is essential for endochondral bone formation in mice

¹ Department of Orthopaedic Surgery and ² Department of Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110
³ International Team for Implantology Research Institute, University of Bern, Bern 3010, Switzerland

Correspondence to D. Patra: patrad{at}wudosis.wustl.edu; or L.J. Sandell: sandelll{at}wudosis.wustl.edu

Site-1 protease (S1P) has an essential function in the conversion of latent, membrane-bound transcription factors to their free, active form. In mammals, abundant expression of S1P in chondrocytes suggests an involvement in chondrocyte function. To determine the requirement of S1P in cartilage and bone development, we have created cartilage-specific S1P knockout mice (S1P^cko). S1P^cko mice exhibit chondrodysplasia and a complete lack of endochondral ossification even though Runx2 expression, Indian hedgehog signaling, and osteoblastogenesis is intact. However, there is a substantial increase in chondrocyte apoptosis in the cartilage of S1P^cko mice. Extraction of type II collagen is substantially lower from S1P^cko cartilage. In S1P^cko mice, the collagen network is disorganized and collagen becomes entrapped in chondrocytes. Ultrastructural analysis reveals that the endoplasmic reticulum (ER) in S1P^cko chondrocytes is engorged and fragmented in a manner characteristic of severe ER stress. These data suggest that S1P activity is necessary for a specialized ER stress response required by chondrocytes for the genesis of normal cartilage and thus endochondral ossification.

E.B. Hunziker's current address is Department of Cranio-Maxillofacial Surgery and Department of Clinical Research, University of Bern, Bern 3010, Switzerland.

Abbreviations used in this paper: Agc1, aggrecan; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy chain binding protein; BSP, bone sialoprotein; Col I, type I collagen; CREBH, cAMP-responsive element binding protein H; E, embryonic day; ERSS, ER stress signaling; IHC, immunohistochemistry; Ihh, Indian hedgehog; MMP, matrix metalloproteinase; OASIS, old astrocyte specifically induced substance; PECAM-1, platelet/endothelial cell adhesion molecule 1; Ptc-1, Patched-1; PTHrP, parathyroid hormone-related peptide; S1P, site-1 protease; SCAP, SREBP cleavage–activating protein; SREBP, sterol regulatory element binding protein; WT, wild type.

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This article has been cited by other articles:

• Yang, G., Sun, Q., Teng, Y., Li, F., Weng, T., Yang, X. (2008). PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1{alpha} signaling and endoplasmic reticulum stress. Development 135: 3587-3597 [Abstract] [Full Text]  
• Patra, D., Xing, X., Davies, S., Bryan, J., Franz, C., Hunziker, E. B., Sandell, L. J. (2007). Site-1 protease is essential for endochondral bone formation in mice. JEM 204: i28-i28 [Full Text]  

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