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Effects of PTHrP on chondrocytes of sika deer antler

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Parathyroid-hormone-related peptide (PTHrP) is an important regulator of chondrocyte differentiation in growth plates but little is known about its role in deer antler cartilage. The aim of the present study was to use the deer antler as a model to determine the possible role of PTHrP in regulating chondrocyte differentiation of deer antler. PTHrP and its receptor PTH1R mRNA were highly expressed in the perichondrium and cartilage of sika deer antler, as shown by in situ hybridization. Chondrocytes of deer antler were identified by toluidine blue staining of glycosaminoglycan and immunocytochemical staining of type II collagen (Col II). Treatment with PTHrP (1–34) reduced the expression of prehypertrophic chondrocyte marker Col IX and hypertrophic chondrocyte marker Col X. In order to confirm the mechanism of action of PTHrP, we initially examined the expression of cyclin D1, Bcl-2 and runt-related transcription factor 2 (Runx2) in sika deer antler by in situ hybridization and found that cyclin D1, Runx2 and Bcl-2 mRNA were also expressed in antler chondrocytes. Exogenous PTHrP induced the expression of cyclin D1 and Bcl-2 mRNA by various signalling pathways, whereas it inhibited Runx2 expression through PKA, p38MAPK, MEK and PI3K signalling pathways. Thus, PTHrP might promote the proliferation of antler chondrocytes and prevent their differentiation; it might furthermore influence the growth and development of sika deer antler.

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  1. Amling M, Neff L, Tanaka S, Inoue D, Kuida K, Weir E, Philbrick WM, Broadus AE, Baron R (1997) Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J Cell Biol 136:205–213

  2. Bartos L, Bubenik GA, Kuzmova E (2012) Endocrine relationships between rank-related behavior and antler growth in deer. Front Biosci (Elite Ed) 4:1111–1126

  3. Beier F, Ali Z, Mok D, Taylor AC, Leask T, Albanese C, Pestell RG, LuValle P (2001) TGFβ and PTHrP control chondrocyte proliferation by activating cyclin D1 expression. Mol Biol Cell 12:3852–3863

  4. Correa D, Hesse E, Seriwatanachai D, Kiviranta R, Saito H, Yamana K, Neff L, Atfi A, Coillard L, Sitara D, Maeda Y, Warming S, Jenkins NA, Copeland NG, Horne WC, Lanske B, Baron R (2010) Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes. Dev Cell 19:533–546

  5. Datta NS, Abou-Samra AB (2009) PTH and PTHrP signaling in osteoblasts. Cell Signal 21:1245–1254

  6. Datta NS, Chen C, Berry JE, McCauley LK (2005) PTHrP signaling targets cyclin D1 and induces osteoblastic cell growth arrest. J Bone Miner Res 20:1051–1064

  7. Datta NS, Pettway GJ, Chen C, Koh AJ, McCauley LK (2007) Cyclin D1 as a target for the proliferative effects of PTH and PTHrP in early osteoblastic cells. J Bone Miner Res 22:951–964

  8. Ding M, Lu Y, Abbassi S, Li F, Li X, Song Y, Geoffroy V, Im HJ, Zheng Q (2012) Targeting Runx2 expression in hypertrophic chondrocytes impairs endochondral ossification during early skeletal development. J Cell Physiol 227:3446–3456

  9. Farquharson C, Jefferies D, Seawright E, Houston B (2001) Regulation of chondrocyte terminal differentiation in the postembryonic growth plate: the role of the PTHrP-Indian hedgehog axis. Endocrinology 142:4131–4140

  10. Faucheux C, Nicholls BM, Allen S, Danks JA, Horton MA, Price JS (2004) Recapitulation of the parathyroid hormone-related peptide-Indian hedgehog pathway in the regenerating deer antler. Dev Dyn 231:88–97

  11. Guo B, Zhang XM, Li SJ, Tian XC, Wang ST, Li DD, Liu JX, Yue ZP (2012) Differential expression and regulation of angiopoietin-3 in mouse uterus during preimplantation period. J Exp Zool B Mol Dev Evol 318:316–324

  12. Guo J, Chung UI, Kondo H, Bringhurst FR, Kronenberg HM (2002) The PTH/PTHrP receptor can delay chondrocyte hypertrophy in vivo without activating phospholipase C. Dev Cell 3:183–194

  13. Ionescu AM, Schwarz EM, Vinson C, Puzas JE, Rosier R, Reynolds PR, O’Keefe RJ (2001) PTHrP modulates chondrocyte differentiation through AP-1 and CREB signaling. J Biol Chem 276:11639–11647

  14. Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM, Segre GV (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024–1026

  15. Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8:277–289

  16. Kierdorf U, Kierdorf H (2012) Antler regrowth as a form of epimorphic regeneration in vertebrates—a comparative view. Front Biosci (Elite Ed) 4:1606–1624

  17. Kierdorf U, Li C, Price JS (2009) Improbable appendages: deer antler renewal as a unique case of mammalian regeneration. Semin Cell Dev Biol 20:535–542

  18. Kindblom JM, Nilsson O, Hurme T, Ohlsson C, Savendahl L (2002) Expression and localization of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP) in the human growth plate during pubertal development. J Endocrinol 174:R1–R6

  19. Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC, Abou-Samra AB, Juppner H, Segre GV, Kronenberg HM (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:663–666

  20. Lee K, Deeds JD, Chiba S, Un-No M, Bond AT, Segre GV (1994) Parathyroid hormone induces sequential c-fos expression in bone cells in vivo: in situ localization of its receptor and c-fos messenger ribonucleic acids. Endocrinology 134:441–450

  21. Li C, Suttie J (2012) Morphogenetic aspects of deer antler development. Front Biosci (Elite Ed) 4:1836–1842

  22. Li C, Clark DE, Lord EA, Stanton JA, Suttie JM (2002) Sampling technique to discriminate the different tissue layers of growing antler tips for gene discovery. Anat Rec 268:125–130

  23. Li TF, Dong Y, Ionescu AM, Rosier RN, Zuscik MJ, Schwarz EM, O’Keefe RJ, Drissi H (2004) Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. Exp Cell Res 299:128–136

  24. Mau E, Whetstone H, Yu C, Hopyan S, Wunder JS, Alman BA (2007) PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms. Dev Biol 305:28–39

  25. Oshima Y, Akiyama T, Hikita A, Iwasawa M, Nagase Y, Nakamura M, Wakeyama H, Kawamura N, Ikeda T, Chung UI, Hennighausen L, Kawaguchi H, Nakamura K, Tanaka S (2008) Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis. J Biol Chem 283:26499–26508

  26. Price J, Allen S (2004) Exploring the mechanisms regulating regeneration of deer antlers. Philos Trans R Soc Lond Biol 359:809–822

  27. Schipani E, Lanske B, Hunzelman J, Luz A, Kovacs CS, Lee K, Pirro A, Kronenberg HM, Jüppner H (1997) Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide. Proc Natl Acad Sci USA 94:13689–13694

  28. Wealthall RJ (2009) In vitro regulation of proliferation and differentiation within a postnatal growth plate of the cranial base by parathyroid hormone-related peptide (PTHrP). J Cell Physiol 219:688–697

  29. Weir EC, Philbrick WM, Amling M, Neff LA, Baron R, Broadus AE (1996) Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc Natl Acad Sci USA 93:10240–10245

  30. Wuelling M, Vortkamp A (2011) Chondrocyte proliferation and differentiation. Endocr Dev 21:1–11

  31. Zhang M, Xie R, Hou W, Wang B, Shen R, Wang X, Wang Q, Zhu T, Jonason JH, Chen D (2009) PTHrP prevents chondrocyte premature hypertrophy by inducing cyclin-D1-dependent Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation. J Cell Sci 122:1382–1389

  32. Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B (2003) Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol 162:833–842

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Correspondence to Qu-Yuan Wang or Zhan-Peng Yue.

Additional information

This work was financially supported by the National Natural Science Foundation of China (31072099 and 31101778), Research Fund for the Doctoral Program of Higher Education of China (20100061110078) and “985” Platform Construction Foundation of Jilin University.

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Guo, B., Wang, S., Duan, C. et al. Effects of PTHrP on chondrocytes of sika deer antler. Cell Tissue Res 354, 451–460 (2013). https://doi.org/10.1007/s00441-013-1670-2

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  • PTHrP
  • Proliferation
  • Differentiation
  • Chondrocyte
  • Sika deer antler