Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation

doi:10.1083/jcb.126.6.1611

This Article

	Full Text (PDF, 7741K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JCB
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Amizuka, N.
	Articles by Karaplis, A. C.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Amizuka, N.
	Articles by Karaplis, A. C.


Social Bookmarking

	What's this?

ARTICLES

Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation

N Amizuka, H Warshawsky, JE Henderson, D Goltzman and AC Karaplis
Department of Medicine, McGill University, Montreal, Quebec, Canada.

To elucidate the role of PTHrP in skeletal development, we examined the proximal tibial epiphysis and metaphysis of wild-type (PTHrP-normal) 18- 19-d-old fetal mice and of chondrodystrophic litter mates homozygous for a disrupted PTHrP allele generated via homologous recombination in embryonic stem cells (PTHrP-depleted). In the PTHrP-normal epiphysis, immunocytochemistry showed PTHrP to be localized in chondrocytes within the resting zone and at the junction between proliferative and hypertrophic zones. In PTHrP-depleted epiphyses, a diminished [3H]thymidine-labeling index was observed in the resting and proliferative zones accounting for reduced numbers of epiphyseal chondrocytes and for a thinner epiphyseal plate. In the mutant hypertrophic zone, enlarged chondrocytes were interspersed with clusters of cells that did not hypertrophy, but resembled resting or proliferative chondrocytes. Although the overall content of type II collagen in the epiphyseal plate was diminished, the lacunae of these non-hypertrophic chondrocytes did react for type II collagen. Moreover, cell membrane-associated chondroitin sulfate immunoreactivity was evident on these cells. Despite the presence of alkaline phosphatase activity on these nonhypertrophic chondrocytes, the adjacent cartilage matrix did not calcify and their persistence accounted for distorted chondrocyte columns and sporadic distribution of calcified cartilage. Consequently, in the metaphysis, bone deposited on the irregular and sparse scaffold of calcified cartilage and resulted in mixed spicules that did not parallel the longitudinal axis of the tibia and were, therefore, inappropriate for bone elongation. Thus, PTHrP appears to modulate both the proliferation and differentiation of chondrocytes and its absence alters the temporal and spatial sequence of epiphyseal cartilage development and of subsequent endochondral bone formation necessary for normal elongation of long bones.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Panda, D., Goltzman, D., Juppner, H., Karaplis, A. C. (2009). TIP39/parathyroid hormone type 2 receptor signaling is a potent inhibitor of chondrocyte proliferation and differentiation. Am. J. Physiol. Endocrinol. Metab. 297: E1125-E1136 [Abstract] [Full Text]
Bai, X.-H., Wang, D.-W., Kong, L., Zhang, Y., Luan, Y., Kobayashi, T., Kronenberg, H. M., Yu, X.-P., Liu, C.-j. (2009). ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor. Mol. Cell. Biol. 29: 4201-4219 [Abstract] [Full Text]
Amizuka, N., Li, M., Hara, K., Kobayashi, M., de Freitas, P. H. L., Ubaidus, S., Oda, K., Akiyama, Y. (2009). Warfarin administration disrupts the assembly of mineralized nodules in the osteoid. J Electron Microsc (Tokyo) 58: 55-65 [Abstract] [Full Text]
Miao, D., Su, H., He, B., Gao, J., Xia, Q., Zhu, M., Gu, Z., Goltzman, D., Karaplis, A. C. (2008). Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein. Proc. Natl. Acad. Sci. USA 105: 20309-20314 [Abstract] [Full Text]
Miedlich, S. U., Abou-Samra, A. B. (2008). Eliminating phosphorylation sites of the parathyroid hormone receptor type 1 differentially affects stimulation of phospholipase C and receptor internalization. Am. J. Physiol. Endocrinol. Metab. 295: E665-E671 [Abstract] [Full Text]
Gupta, A., Valimaki, V.-V., J Valimaki, M., Loyttyniemi, E., Richard, M., L Bukka, P., Goltzman, D., C Karaplis, A. (2008). Variable number of tandem repeats polymorphism in parathyroid hormone-related protein as predictor of peak bone mass in young healthy Finnish males. Eur J Endocrinol 158: 755-764 [Abstract] [Full Text]
Frazier, K., Thomas, R., Scicchitano, M., Mirabile, R., Boyce, R., Zimmerman, D., Grygielko, E., Nold, J., DeGouville, A.-C., Huet, S., Laping, N., Gellibert, F. (2007). Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats. Toxicol Pathol 35: 284-295 [Abstract] [Full Text]
Kamiya, N., Watanabe, H., Habuchi, H., Takagi, H., Shinomura, T., Shimizu, K., Kimata, K. (2006). Versican/PG-M Regulates Chondrogenesis as an Extracellular Matrix Molecule Crucial for Mesenchymal Condensation. J. Biol. Chem. 281: 2390-2400 [Abstract] [Full Text]
Zhang, R., Murakami, S., Coustry, F., Wang, Y., de Crombrugghe, B. (2006). Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. Proc. Natl. Acad. Sci. USA 103: 365-370 [Abstract] [Full Text]
Tchetina, E. V., Antoniou, J., Tanzer, M., Zukor, D. J., Poole, A. R. (2006). Transforming Growth Factor-{beta}2 Suppresses Collagen Cleavage in Cultured Human Osteoarthritic Cartilage, Reduces Expression of Genes Associated with Chondrocyte Hypertrophy and Degradation, and Increases Prostaglandin E2 Production. Am. J. Pathol. 168: 131-140 [Abstract] [Full Text]
Kronenberg, H. M. (2005). How PTHrP Controls Growth Plate Chondrocytes. IBMS BoneKEy 2: 7-15 [Full Text]
Godler, D. E., Stein, A. N., Bakharevski, O., Lindsay, M. M. L., Ryan, P. F. J. (2005). Parathyroid hormone-related peptide expression in rat collagen-induced arthritis. Rheumatology (Oxford) 44: 1122-1131 [Abstract] [Full Text]
Tanaka, N., Ohno, S., Honda, K., Tanimoto, K., Doi, T., Ohno-Nakahara, M., Tafolla, E., Kapila, S., Tanne, K. (2005). Cyclic Mechanical Strain Regulates the PTHrP Expression in Cultured Chondrocytes via Activation of the Ca2+ Channel. JDR 84: 64-68 [Abstract] [Full Text]
Miao, D., Li, J., Xue, Y., Su, H., Karaplis, A. C., Goltzman, D. (2004). Parathyroid Hormone-Related Peptide Is Required for Increased Trabecular Bone Volume in Parathyroid Hormone-Null Mice. Endocrinology 145: 3554-3562 [Abstract] [Full Text]
Valverde-Franco, G., Liu, H., Davidson, D., Chai, S., Valderrama-Carvajal, H., Goltzman, D., Ornitz, D. M., Henderson, J. E. (2004). Defective bone mineralization and osteopenia in young adult FGFR3-/- mice. Hum Mol Genet 13: 271-284 [Abstract] [Full Text]
Koshizuka, Y., Yamada, T., Hoshi, K., Ogasawara, T., Chung, U.-i., Kawano, H., Nakamura, Y., Nakamura, K., Ikegawa, S., Kawaguchi, H. (2003). Cystatin 10, a Novel Chondrocyte-specific Protein, May Promote the Last Steps of the Chondrocyte Differentiation Pathway. J. Biol. Chem. 278: 48259-48266 [Abstract] [Full Text]
Reddi, A H (2003). Cartilage morphogenetic proteins: role in joint development, homoeostasis, and regeneration. Ann Rheum Dis 62: ii73-78 [Abstract] [Full Text]
Germain-Lee, E. L., Groman, J., Crane, J. L., Jan de Beur, S. M., Levine, M. A. (2003). Growth Hormone Deficiency in Pseudohypoparathyroidism Type 1a: Another Manifestation of Multihormone Resistance. J. Clin. Endocrinol. Metab. 88: 4059-4069 [Abstract] [Full Text]
Li, X., Schwarz, E. M., Zuscik, M. J., Rosier, R. N., Ionescu, A. M., Puzas, J. E., Drissi, H., Sheu, T.-J., O'Keefe, R. J. (2003). Retinoic Acid Stimulates Chondrocyte Differentiation and Enhances Bone Morphogenetic Protein Effects through Induction of Smad1 and Smad5. Endocrinology 144: 2514-2523 [Abstract] [Full Text]
Scheijen, B., Bronk, M., van der Meer, T., Bernards, R. (2003). Constitutive E2F1 Overexpression Delays Endochondral Bone Formation by Inhibiting Chondrocyte Differentiation. Mol. Cell. Biol. 23: 3656-3668 [Abstract] [Full Text]
Beier, F., LuValle, P. (2002). The Cyclin D1 and Cyclin A Genes Are Targets of Activated PTH/PTHrP Receptors in Jansen's Metaphyseal Chondrodysplasia. Mol. Endocrinol. 16: 2163-2173 [Abstract] [Full Text]
Takeda, H., Takami, M., Oguni, T., Tsuji, T., Yoneda, K., Sato, H., Ihara, N., Itoh, T., Kata, S. R., Mishina, Y., Womack, J. E., Moritomo, Y., Sugimoto, Y., Kunieda, T. (2002). Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism. Proc. Natl. Acad. Sci. USA 99: 10549-10554 [Abstract] [Full Text]
Ornitz, D. M., Marie, P. J. (2002). FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16: 1446-1465 [Full Text]
Beier, F., Ali, Z., Mok, D., Taylor, A. C., Leask, T., Albanese, C., Pestell, R. G., LuValle, P. (2001). TGFbeta and PTHrP Control Chondrocyte Proliferation by Activating Cyclin D1 Expression. Mol. Biol. Cell 12: 3852-3863 [Abstract] [Full Text]
Minina, E., Wenzel, H. M., Kreschel, C., Karp, S., Gaffield, W., McMahon, A. P., Vortkamp, A. (2001). BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128: 4523-4534 [Abstract] [Full Text]
Chan, G. K., Deckelbaum, R. A., Bolivar, I., Goltzman, D., Karaplis, A. C. (2001). PTHrP Inhibits Adipocyte Differentiation by Down-Regulating PPAR{gamma} Activity via a MAPK-Dependent Pathway. Endocrinology 142: 4900-4909 [Abstract] [Full Text]
He, B., Deckelbaum, R. A., Miao, D., Lipman, M. L., Pollak, M., Goltzman, D., Karaplis, A. C. (2001). Tissue-Specific Targeting of the Pthrp Gene: The Generation of Mice with Floxed Alleles. Endocrinology 142: 2070-2077 [Abstract] [Full Text]
Chen, L., Li, C., Qiao, W., Xu, X., Deng, C. (2001). A Ser365{->}Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 10: 457-465 [Abstract] [Full Text]
Ouyang, H., Franceschi, R. T., McCauley, L. K., Wang, D., Somerman, M. J. (2000). Parathyroid Hormone-Related Protein Down-Regulates Bone Sialoprotein Gene Expression in Cementoblasts: Role of the Protein Kinase A Pathway. Endocrinology 141: 4671-4680 [Abstract] [Full Text]
El Abdaimi, K., Papavasiliou, V., Goltzman, D., Kremer, R. (2000). Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes. Am. J. Physiol. Cell Physiol. 279: C1230-C1238 [Abstract] [Full Text]
Hoare, S. R. J., Rubin, D. A., Juppner, H., Usdin, T. B. (2000). Evaluating the Ligand Specificity of Zebrafish Parathyroid Hormone (PTH) Receptors: Comparison of PTH, PTH-Related Protein, and Tuberoinfundibular Peptide of 39 Residues. Endocrinology 141: 3080-3086 [Abstract] [Full Text]
Turner, P. R., Mefford, S., Christakos, S., Nissenson, R. A. (2000). Apoptosis Mediated by Activation of the G Protein-Coupled Receptor for Parathyroid Hormone (PTH)/ PTH-Related Protein (PTHrP). Mol. Endocrinol. 14: 241-254 [Abstract] [Full Text]
Hartmann, C, Tabin, C. (2000). Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127: 3141-3159 [Abstract]
Thomas, D., Sunters, A, Gentry, A, Grigoriadis, A. (2000). Inhibition of chondrocyte differentiation in vitro by constitutive and inducible overexpression of the c-fos proto-oncogene. J. Cell Sci. 113: 439-450 [Abstract]
M. Dougherty, K., Blomme, E. A. G., Koh, A. J., Henderson, J. E., Pienta, K. J., Rosol, T. J., McCauley, L. K. (1999). Parathyroid Hormone-related Protein as a Growth Regulator of Prostate Carcinoma. Cancer Res. 59: 6015-6022 [Abstract] [Full Text]
McEwen, D. G., Green, R. P., Naski, M. C., Towler, D. A., Ornitz, D. M. (1999). Fibroblast Growth Factor Receptor 3 Gene Transcription Is Suppressed by Cyclic Adenosine 3',5'-Monophosphate. IDENTIFICATION OF A CHONDROCYTIC REGULATORY ELEMENT. J. Biol. Chem. 274: 30934-30942 [Abstract] [Full Text]
Beier, F., Taylor, A. C., LuValle, P. (1999). The Raf-1/MEK/ERK Pathway Regulates the Expression of the p21Cip1/Waf1 Gene in Chondrocytes. J. Biol. Chem. 274: 30273-30279 [Abstract] [Full Text]
St-Jacques, B., Hammerschmidt, M., McMahon, A. P. (1999). Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13: 2072-2086 [Abstract] [Full Text]
Harvey, A. K., Yu, X.-P., Frolik, C. A., Chandrasekhar, S. (1999). Parathyroid Hormone-(1-34) Enhances Aggrecan Synthesis via an Insulin-like Growth Factor-I Pathway. J. Biol. Chem. 274: 23249-23255 [Abstract] [Full Text]
Iwamoto, M., Enomoto-Iwamoto, M., Kurisu, K. (1999). Actions of Hedgehog Proteins on Skeletal Cells. CROBM 10: 477-486 [Abstract] [Full Text]
Lam, M. H.�C., House, C. M., Tiganis, T., Mitchelhill, K. I., Sarcevic, B., Cures, A., Ramsay, R., Kemp, B. E., Martin, T. J., Gillespie, M. T. (1999). Phosphorylation at the Cyclin-dependent Kinases Site (Thr85) of Parathyroid Hormone-related Protein Negatively Regulates Its Nuclear Localization. J. Biol. Chem. 274: 18559-18566 [Abstract] [Full Text]
Hoare, S. R.�J., de Vries, G., Usdin, T. B. (1999). Measurement of Agonist and Antagonist Ligand-Binding Parameters at the Human Parathyroid Hormone Type 1�Receptor: Evaluation of Receptor States and Modulation by Guanine Nucleotide. J. Pharmacol. Exp. Ther. 289: 1323-1333 [Abstract] [Full Text]
Serra, R., Karaplis, A., Sohn, P. (1999). Parathyroid Hormone-related Peptide (PTHrP)-dependent and -independent Effects of Transforming Growth Factor {beta} (TGF-{beta}) on Endochondral Bone Formation. JCB 145: 783-794 [Abstract] [Full Text]
Kawashima-Ohya, Y., Kuruta, Y., Yan, W., Kawamoto, T., Noshiro, M., Kato, Y. (1999). Retinol-Binding Protein Is Produced by Rabbit Chondrocytes and Responds to Parathyroid Hormone (PTH)/PTH-Related Peptide-Cyclic Adenosine Monophosphate Pathway. Endocrinology 140: 1075-1081 [Abstract] [Full Text]
Crowe, R, Zikherman, J, Niswander, L (1999). Delta-1 negatively regulates the transition from prehypertrophic to hypertrophic chondrocytes during cartilage formation. Development 126: 987-998 [Abstract]
Lanske, B., Divieti, P., Kovacs, C. S., Pirro, A., Landis, W. J., Krane, S. M., Bringhurst, F. R., Kronenberg, H. M. (1998). The Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mediates Actions of Both Ligands in Murine Bone. Endocrinology 139: 5194-5204 [Abstract] [Full Text]
Chung, U.-i., Lanske, B., Lee, K., Li, E., Kronenberg, H. (1998). The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. Proc. Natl. Acad. Sci. USA 95: 13030-13035 [Abstract] [Full Text]
Meerovitch, K., Wing, S., Goltzman, D. (1998). Proparathyroid Hormone-related Protein Is Associated with the Chaperone Protein BiP and Undergoes Proteasome-mediated Degradation. J. Biol. Chem. 273: 21025-21030 [Abstract] [Full Text]
Yasoda, A., Ogawa, Y., Suda, M., Tamura, N., Mori, K., Sakuma, Y., Chusho, H., Shiota, K., Tanaka, K., Nakao, K. (1998). Natriuretic Peptide Regulation of Endochondral Ossification. EVIDENCE FOR POSSIBLE ROLES OF THE C-TYPE NATRIURETIC PEPTIDE/GUANYLYL CYCLASE-B PATHWAY. J. Biol. Chem. 273: 11695-11700 [Abstract] [Full Text]
Kawashima-Ohya, Y., Satakeda, H., Kuruta, Y., Kawamoto, T., Yan, W., Akagawa, Y., Hayakawa, T., Noshiro, M., Okada, Y., Nakamura, S., Kato, Y. (1998). Effects of Parathyroid Hormone (PTH) and PTH-Related Peptide on Expressions of Matrix Metalloproteinase- 2, -3, and -9 in Growth Plate Chondrocyte Cultures. Endocrinology 139: 2120-2127 [Abstract] [Full Text]
Rihani-Bisharat, S., Maor, G., Lewinson, D. (1998). In Vivo Anabolic Effects of Parathyroid Hormone (PTH) 28-48 and N-Terminal Fragments of PTH and PTH-Related Protein on Neonatal Mouse Bones. Endocrinology 139: 974-981 [Abstract] [Full Text]
Eggenberger, M., McKinney, R. A., Fischer, J. A., Muff, R. (1998). Differential Expression of Calcitonin and Parathyroid Hormone/Parathyroid Hormone-Related Protein Receptors in P19 Embryonic Carcinoma Cells Treated with Retinoic Acid. Endocrinology 139: 1023-1030 [Abstract] [Full Text]
Romano, P., Wang, J, O'Keefe, R., Puzas, J., Rosier, R., Reynolds, P. (1998). HiPER1, a phosphatase of the endoplasmic reticulum with a role in chondrocyte maturation. J. Cell Sci. 111: 803-813 [Abstract]
Serra, R., Johnson, M., Filvaroff, E. H., LaBorde, J., Sheehan, D. M., Derynck, R., Moses, H. L. (1997). Expression of a Truncated, Kinase-Defective TGF-{beta} Type II Receptor in Mouse Skeletal Tissue Promotes Terminal Chondrocyte Differentiation and Osteoarthritis. JCB 139: 541-552 [Abstract] [Full Text]
Jono, S., Nishizawa, Y., Shioi, A., Morii, H. (1997). Parathyroid Hormone�Related Peptide as a Local Regulator of Vascular Calcification: Its Inhibitory Action on In Vitro Calcification by Bovine Vascular Smooth Muscle Cells. Arterioscler. Thromb. Vasc. Bio. 17: 1135-1142 [Abstract] [Full Text]
Meerovitch, K., Wing, S., Goltzman, D. (1997). Preproparathyroid Hormone-related Protein, a Secreted Peptide, Is a Substrate for the Ubiquitin Proteolytic System. J. Biol. Chem. 272: 6706-6713 [Abstract] [Full Text]
Amling, M., Neff, L., Tanaka, S., Inoue, D., Kuida, K., Weir, E., Philbrick, W. M., Broadus, A. E., Baron, R. (1997). Bcl-2 Lies Downstream of Parathyroid Hormone-related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development. JCB 136: 205-213 [Abstract] [Full Text]
Stott, N., Chuong, C. (1997). Dual action of sonic hedgehog on chondrocyte hypertrophy: retrovirus mediated ectopic sonic hedgehog expression in limb bud micromass culture induces novel cartilage nodules that are positive for alkaline phosphatase and type X collagen. J. Cell Sci. 110: 2691-2701 [Abstract]
Amizuka, N., Lee, H. S., Kwan, M. Y., Arazani, A., Warshawsky, H., Hendy, G. N., Ozawa, H., White, J. H., Goltzman, D. (1997). Cell-Specific Expression of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene in Kidney from Kidney-Specific and Ubiquitous Promoters. Endocrinology 138: 469-481 [Abstract] [Full Text]
Levi, G, Topilko, P, Schneider-Maunoury, S, Lasagna, M, Mantero, S, Cancedda, R, Charnay, P (1996). Defective bone formation in Krox-20 mutant mice. Development 122: 113-120 [Abstract]
Schipani, E, Kruse, K, Juppner, H (1995). A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268: 98-100 [Abstract]
Zhen, X., Wei, L., Wu, Q., Zhang, Y., Chen, Q. (2001). Mitogen-activated Protein Kinase p38 Mediates Regulation of Chondrocyte Differentiation by Parathyroid Hormone. J. Biol. Chem. 276: 4879-4885 [Abstract] [Full Text]
Ionescu, A. M., Schwarz, E. M., Vinson, C., Puzas, J. E., Rosier, R., Reynolds, P. R., O'Keefe, R. J. (2001). PTHrP Modulates Chondrocyte Differentiation through AP-1 and CREB Signaling. J. Biol. Chem. 276: 11639-11647 [Abstract] [Full Text]
Wang, D., Canaff, L., Davidson, D., Corluka, A., Liu, H., Hendy, G. N., Henderson, J. E. (2001). Alterations in the Sensing and Transport of Phosphate and Calcium by Differentiating Chondrocytes. J. Biol. Chem. 276: 33995-34005 [Abstract] [Full Text]
Ito, H., Akiyama, H., Iguchi, H., Iyama, K.-i., Miyamoto, M., Ohsawa, K., Nakamura, T. (2001). Molecular Cloning and Biological Activity of a Novel Lysyl Oxidase-related Gene Expressed in Cartilage. J. Biol. Chem. 276: 24023-24029 [Abstract] [Full Text]
Aarts, M. M., Davidson, D., Corluka, A., Petroulakis, E., Guo, J., Bringhurst, F. R., Galipeau, J., Henderson, J. E. (2001). Parathyroid Hormone-related Protein Promotes Quiescence and Survival of Serum-deprived Chondrocytes by Inhibiting rRNA Synthesis. J. Biol. Chem. 276: 37934-37943 [Abstract] [Full Text]