Caspase-3 and -7 are generally known for their central role in the execution of apoptosis. However, their function is not limited to apoptosis and under specific conditions activation has been linked to proliferation or differentiation of specialised cell types. In the present study, we followed the localisation of the activated form of caspase-7 during intramembranous (alveolar and mandibular bones) and endochondral (long bones of limbs) ossification in mice. In both bone types, the activated form of caspase-7 was detected from the beginning of ossification during embryonic development and persisted postnatally. The bone status was investigated by microCT in both wild-type and caspase-7-deficient adult mice. Intramembranous bone in mutant mice displayed a statistically significant decrease in volume while the mineral density was not altered. Conversely, endochondral bone showed constant volume but a significant decrease in mineral density in caspase-7 knock-out mice. Cleaved caspase-7 was present in a number of cells that did not show signs of apoptosis. PCR array analysis of the mandibular bone of caspase-7-deficient versus wild-type mice pointed to a significant decrease in mRNA levels for Msx1 and Smad1 in early bone formation. These observations might explain the decrease in the alveolar bone volume of adult knock-out mice. In conclusion, this study is the first to report a non-apoptotic function of caspase-7 in osteogenesis and also demonstrates further specificities in endochondral versus intramembranous ossification.

] Inflammation Research Centre VIB Ghent Belgium [2] Department of Molecular Biology Ghent University Ghent Belgium

] INSERM UMR 1109 team Osteoarticular and Dental Regenerative NanoMedicine Strasbourg France [2] Faculté de chirurgie dentaire Université de Strasbourg Strasbourg France

] Institute of Animal Physiology and Genetics CAS v v i Brno Czech Republic [2] Department of Physiology University of Veterinary and Pharmaceutical Sciences Brno Czech Republic

Department of Craniofacial Development and Stem Cell Biology King's College London London UK

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Houde C, Banks KG, Coulombe N, Rasper D, Grimm E, Roy S, et al. Caspase-7 expanded function and intrinsic expression level underlies strain-specific brain phenotype of caspase-3-null mice. J Neurosci. 2004;24:9977–9984. PubMed PMC

Choudhury S, Bhootada Y, Gorbatyuk O, Gorbatyuk M. Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration. Cell Death Dis. 2013;4:e528. PubMed PMC

Matalova E, Vanden Berghe T, Svandova E, Vandenabeele P, Healy C, Sharpe PT, et al. Caspase-7 in molar tooth development. Arch Oral Biol. 2012;57:1474–1481. PubMed

Matalova E, Lesot H, Svandova E, Vanden Berghe T, Sharpe PT, Healy C, et al. Caspase-7 participates in differentiation of cells forming dental hard tissues. Dev Growth Differ. 2013;55:615–621. PubMed

Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P. Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 2007;14:44–55. PubMed

Chung UI, Kawaguchi H, Takato T, Nakamura K. Distinct osteogenic mechanisms of bones of distinct origins. J Orthop Sci. 2004;9:410–414. PubMed

Groeneveld EHJ, Burger EH. Bone morphogenetic proteins in human bone regeneration. Eur J Endocrinol. 2000;142:9–21. PubMed

Marie PJ. Fibroblast growth factor signaling controlling bone formation: an update. Gene. 2012;498:1–4. PubMed

Spinella-Jaegle S, Rawadi G, Kawai S, Gallea S, Faucheu C, Mollat P, et al. Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci. 2001;114:2085–2094. PubMed

Yang YQ, Tan YY, Wong R, Wenden A, Zhang LK, Rabie AB. The role of vascular endothelial growth factor in ossification. Int J Oral Sci. 2012;4:64–68. PubMed PMC

Clarkin CE, Gerstenfeld LC. VEGF and bone cell signalling: an essential vessel for communication. Cell Biochem Funct. 2013;31:1–11. PubMed

Chen G, Deng C, Li YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 2012;8:272–288. PubMed PMC

Bendall AJ, Abate-Shen C. Roles for Msx and Dlx homeoproteins in vertebrate development. Gene. 2000;247:17–31. PubMed

Wright E, Hargrave MR, Christiansen J, Cooper L, Kun J, Evans T, et al. The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nat Genet. 1995;9:15–20. PubMed

Komori T. Runx2, a multifunctional transcription factor in skeletal development. J Cell Biochem. 2002;87:1–8. PubMed

Diep L, Matalova E, Mitsiadis TA, Tucker AS. Contribution of the tooth bud mesenchyme to alveolar bone. J Exp Zool B Mol Dev Evol. 2009;312B:510–517. PubMed

Lungová V, Radlanski RJ, Tucker AS, Renz H, Míšek I, Matalová E. Tooth-bone morphogenesis during postnatal stages of mouse first molar development. J Anat. 2011;218:699–716. PubMed PMC

Crawford ED, Wells JA. Caspase substrates and cellular remodeling. Annu Rev Biochem. 2011;80:1055–1087. PubMed

Schwerk C, Schulze-Osthoff K. Non-apoptotic functions of caspases in cellular proliferation and differentiation. Biochem Pharmacol. 2003;66:1453–1458. PubMed

Ramaesh T, Bard JB. The growth and morphogenesis of the early mouse mandible: a quantitative analysis. J Anat. 2003;203:213–222. PubMed PMC

Kim IS, Otto F, Zabel B, Mundlos S. Regulation of chondrocyte differentiation by Cbfa1. Mech Dev. 1999;80:159–170. PubMed

Aghaloo TL, Chaichanasakul T, Bezouglaia O, Kang B, Franco R, Dry SM, et al. Osteogenic potential of mandibular versus long-bone marrow stromal cells. J Dent Res. 2010;89:1293–1298. PubMed PMC

Kashima TG, Nishiyama T, Shimazu K, Shimazaki M, Kii I, Grigoriadis AE, et al. Periostin, a novel marker of intramembranous ossification, is expressed in fibrous dysplasia and in c-Fos-over expressing bone lesions. Hum Pathol. 2009;40:226–237. PubMed

Suttapreyasri S, Koontongkaew S, Phongdara A, Leggat U. Expression of bone morphogenetic proteins in normal human intramembranous and endochondral bones. Int J Oral Maxillofac Surg. 2006;35:444–452. PubMed

De Spiegelaere W, Cornillie P, Casteleyn C, Burvenich C, Van den Broeck W. Detection of hypoxia inducible factors and angiogenic growth factors during metal endochondral and intramembranous ossification. Anat Histol Embryol. 2010;39:376–384. PubMed

Kugimiya F, Kawaguchi H, Kamekura S, Chikuda H, Ohba S, Yano F, et al. Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation. J Biol Chem. 2005;280:35704–35712. PubMed

Musch T, Öz Y, Lyko F, Breiling A. Nucleoside drugs induce cellular differentiation by caspase-dependent degradation of stem cell factors. PLoS One. 2010;5:e10726. PubMed PMC

Talanian RV, Quinlan C, Trautz S, Hackett MC, Mankovich JA, Banach D, et al. Substrate specificities of caspase family proteases. J Biol Chem. 1997;272:9677–9682. PubMed

Lakhani SA, Masud A, Kuida K, Porter GA, Jr, Booth CJ, Mehal WZ, et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006;311:847–851. PubMed PMC

Miura M, Chen XD, Allen MR, Bi Y, Gronthos S, Seo BM, et al. A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells. J Clin Invest. 2004;114:1704–1713. PubMed PMC

Nakatsumi H, Yonehara S. Identification of functional regions defining different activity in caspase-3 and caspase-7 within cells. J Biol Chem. 2010;285:25418–25425. PubMed PMC

Walsh JG, Cullen SP, Sheridan C, Lüthi AU, Gerner C, Martin SJ. Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc Natl Acad Sci USA. 2008;105:12815–12819. PubMed PMC

Chandler JM, Cohen GM, MacFarlane M. Different subcellular distribution of caspase-3 and caspase-7 following Fas-induced apoptosis in mouse liver. J Biol Chem. 1998;273:10815–10818. PubMed

Demon D, Van Damme P, Vanden Berghe T, Vandekerckhove J, Declercq W, Gevaert K, et al. Caspase substrates: easily caught in deep waters. Trends Biotechnol. 2009;27:680–688. PubMed

Moriishi T, Maruyama Z, Fukuyama R, Ito M, Miyazaki T, Kitaura H, et al. Overexpression of Bcl2 in osteoblasts inhibits osteoblast differentiation and induces osteocyte apoptosis. PLoS One. 2011;6:e27487. PubMed PMC

Tamburstuen MV, Reseland JE, Spahr A, Brookes SJ, Kvalheim G, Slaby I, et al. Ameloblastin expression and putative autoregulation in mesenchymal cells suggest a role in early bone formation and repair. Bone. 2011;48:406–413. PubMed PMC

Suzuki S, Haruyama N, Nishimura F, Kulkarni AB. Dentin sialophosphoprotein and dentin matrixprotein-1: two highly phosphorylated proteins in mineralized tissues. Arch Oral Biol. 2012;57:1165–1175. PubMed PMC

Korpi JT, Aström P, Lehtonen N, Tjäderhane L, Kallio-Pulkkinen S, Siponen M, et al. Healing of extraction sockets in collagenase-2 (matrix metalloproteinase-8)-deficient mice. Eur J Oral Sci. 2009;117:248–254. PubMed

Wang M, Jin H, Tang D, Huang S, Zuscik MJ, Chen D. Smad1 plays an essential role in bone development and postnatal bone formation. Osteoarthritis Cartilage. 2011;19:751–762. PubMed PMC

Nohe A, Keating E, Knaus P, Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal. 2004;16:291–299. PubMed

Hellingman CA, Davidson EN, Koevoet W, Vitters EL, van den Berg WB, van Osch GJ, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A. 2011;17:1157–1167. PubMed

Wise GE, He H, Gutierrez DL, Ring S, Yao S. Requirement of alveolar bone formation for eruption of rat molars. Eur J Oral Sci. 2011;119:333–338. PubMed PMC

Mishina Y, Starbuck MW, Gentile MA, Fukuda T, Kasparcova V, Seedor JG, et al. Bone morphogenetic protein type IA receptor signalling regulates postnatal osteoblast function and bone remodeling. J Biol Chem. 2004;279:27560–27566. PubMed

Golub EE, Boesze-Battaglia K. The role of alkaline phosphatase in mineralization. Curr Opin Orthop. 2007;18:444–448.

San Miguel SM, Goseki-Sone M, Sugiyama E, Watanabe H, Yanagishita M, Ishikawa I. Tissue-non-specific alkaline phosphatase mRNA expression and alkaline phosphatase activity following application of retinoic acid in cultured human dental pulp cells. Arch Oral Biol. 1999;44:861–869. PubMed

Gianni M, Studer M, Carpani G, Terao M, Garattini E. Retinoic acid induces liver/bone/kidney-type alkaline phosphatase gene expression in F9 teratocarcinoma cells. Biochem J. 1991;274:673–678. PubMed PMC

Rambaldi A, Terao M, Bettoni S, Bassan R, Battista R, Barbui T, et al. Differences in the expression of alkaline phosphatase mRNA in chronic myelogenous leukemia and paroxysmal nocturnal hemoglobinuria polymorphonuclear leukocytes. Blood. 1989;73:1113–1115. PubMed

Kyeyune-Nyombi E, Nicolas V, Strong DD, Farley J. Paradoxical effects of phosphate to directly regulate the level of skeletal alkaline phosphatase activity in human osteosarcoma (SaOS-2) cells and inversely regulate the level of skeletal alkaline phosphatase mRNA. Calcif Tissue Int. 1995;56:154–159. PubMed

Zhivotovsky B, Samali A, Gahm A, Orrenius S. Caspases: their intracellular localization and translocation during apoptosis. Cell Death Differ. 1999;6:644–651. PubMed

Faleiro L, Lazebnik Y. Caspases disrupt the nuclear-cytoplasmic barrier. J Cell Biol. 2000;151:951–959. PubMed PMC

Germain M, Affar EB, D'Amours D, Dixit VM, Salvesen GS, Poirier GG. Cleavage of automodified poly (ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J Biol Chem. 1999;274:28379–28384. PubMed

Faragher AJ, Sun XM, Butterworth M, Harper N, Mulheran M, Ruchaud S, et al. Death receptor-induced apoptosis reveals a novel interplay between the chromosomal passenger complex and CENP-C during interphase. Mol Biol Cell. 2007;18:1337–1347. PubMed PMC

Liu X, Zou H, Slaughter C, Wang X. DFF a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89:175–184. PubMed

Obara N, Lesot H. Subcellular localization of beta-catenin and cadherin expression in the cap-stage enamel organ of the mouse molar. Histochem Cell Biol. 2004;121:351–358. PubMed

Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity. 2011;35:908–918. PubMed

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