Abstract
Mammalian bones have three distinct origins (paraxial mesoderm, lateral plate mesoderm, and neural crest) and undergo two different modes of formation (intramembranous and endochondral). Bones derived from the paraxial mesoderm and lateral plate mesoderm mainly form through the endochondral process. During this process, hypertrophic chondrocytes play a vital role in inducing osteogenesis. So far, a number of published papers have provided evidence that chondrocyte hypertrophy and osteoblast differentiation are controlled by a variety of signaling pathways and factors; however, little is known about their hierarchy (which are upstream? which are most potent?). In this review, we discuss the signaling pathways and transcriptional factors regulating chondrocyte hypertrophy and osteoblast differentiation based on the evidence that has been reported and confirmed by multiple independent groups. We then discuss which factor would provide the most coherent evidence for its role in endochondral ossification.
Similar content being viewed by others
References
Kronenberg HM (2003) Developmental regulation of the growth plate. Nature (Lond) 423:332–336
Colnot C, Lu C, Hu D, Helms JA (2004) Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. Dev Biol 269:55–69
Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ et al (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature (Lond) 425:836–841
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature (Lond) 425:841–846
Chung UI, Schipani E, McMahon AP, Kronenberg HM (2001) Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest 107:295–304
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
Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC et al (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:663–666
Schipani E, Lanske B, Hunzelman J, Luz A, Kovacs CS, Lee K, Pirro A, Kronenberg HM, Juppner 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
Chung UI, 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
Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273:613–622
St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13:2072–2086
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
Bastepe M, Weinstein LS, Ogata N, Kawaguchi H, Juppner H, Kronenberg HM, Chung UI (2004) Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci USA 101:14794–14799
Kobayashi T, Chung UI, Schipani E, Starbuck M, Karsenty G, Katagiri T, Goad DL, Lanske B, Kronenberg HM (2002) PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. Development (Camb) 129:2977–2986
Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087
Koziel L, Wuelling M, Schneider S, Vortkamp A (2005) Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development (Camb) 132:5249–5260
Huelsken J, Birchmeier W (2001) New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev 11:547–553
Wodarz A, Nusse R (1998) Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14:59–88
Mao J, Wang J, Liu B, Pan W, Farr GH 3rd, Flynn C, Yuan H, Takada S, Kimelman D, Li L et al (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7:801–809
Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature (Lond) 407:535–538
Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature (Lond) 407:530–535
Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C (1998) Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature (Lond) 391:357–362
Chamorro MN, Schwartz DR, Vonica A, Brivanlou AH, Cho KR, Varmus HE (2005) FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J 24:73–84
Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama T (2004) DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene 23:8520–8526
Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3:683–686
Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature (Lond) 411:321–325
Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X (2001) Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol 11:951–961
Veeman MT, Axelrod JD, Moon RT (2003) A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 5:367–377
Andrade AC, Nilsson O, Barnes KM, Baron J (2007) Wnt gene expression in the post-natal growth plate: regulation with chondrocyte differentiation. Bone (NY) 40:1361–1369
Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR et al (2004) Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev 18:1072–1087
Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, Yamada Y, Costantini F, Wakisaka S, Pacifici M et al (2005) Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem 280:19185–19195
Enomoto-Iwamoto M, Kitagaki J, Koyama E, Tamamura Y, Wu C, Kanatani N, Koike T, Okada H, Komori T, Yoneda T et al (2002) The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev Biol 251:142–156
Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750
Mak KK, Chen MH, Day TF, Chuang PT, Yang Y (2006) Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development (Camb) 133:3695–3707
Yang Y, Topol L, Lee H, Wu J (2003) Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development (Camb) 130:1003–1015
Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791
Pogue R, Lyons K (2006) BMP signaling in the cartilage growth plate. Curr Top Dev Biol 76:1–48
Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature (Lond) 425:577–584
Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783–2810
Pathi S, Rutenberg JB, Johnson RL, Vortkamp A (1999) Interaction of Ihh and BMP/Noggin signaling during cartilage differentiation. Dev Biol 209:239–253
Zou H, Wieser R, Massague J, Niswander L (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev 11:2191–2203
Daluiski A, Engstrand T, Bahamonde ME, Gamer LW, Agius E, Stevenson SL, Cox K, Rosen V, Lyons KM (2001) Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 27:84–88
Haaijman A, Burger EH, Goei SW, Nelles L, ten Dijke P, Huylebroeck D, Bronckers AL (2000) Correlation between ALK-6 (BMPR-IB) distribution and responsiveness to osteogenic protein-1 (BMP-7) in embryonic mouse bone rudiments. Growth Factors 17:177–192
Lyons KM, Pelton RW, Hogan BL (1990) Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2A (BMP-2A). Development (Camb) 109:833–844
Lyons KM, Hogan BL, Robertson EJ (1995) Colocalization of BMP 7 and BMP 2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development. Mech Dev 50:71–83
Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A (2001) BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development (Camb) 128:4523–4534
Sakou T, Onishi T, Yamamoto T, Nagamine T, Sampath T, Ten Dijke P (1999) Localization of Smads, the TGF-beta family intracellular signaling components during endochondral ossification. J Bone Miner Res 14:1145–1152
Yi SE, LaPolt PS, Yoon BS, Chen JY, Lu JK, Lyons KM (2001) The type I BMP receptor BmprIB is essential for female reproductive function. Proc Natl Acad Sci USA 98:7994–7999
Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci USA 102:5062–5067
Retting KN, Song B, Yoon BS, Lyons KM (2009) BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development (Camb) 136:1093–1104
Grimsrud CD, Romano PR, D’Souza M, Puzas JE, Reynolds PR, Rosier RN, O’Keefe RJ (1999) BMP-6 is an autocrine stimulator of chondrocyte differentiation. J Bone Miner Res 14:475–482
Kobayashi T, Lyons KM, McMahon AP, Kronenberg HM (2005) BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci USA 102:18023–18027
Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V, Tabin CJ (2006) Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2:e216
Yoon BS, Pogue R, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM (2006) BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways. Development (Camb) 133:4667–4678
Ellingsworth LR, Brennan JE, Fok K, Rosen DM, Bentz H, Piez KA, Seyedin SM (1986) Antibodies to the N-terminal portion of cartilage-inducing factor A and transforming growth factor beta. Immunohistochemical localization and association with differentiating cells. J Biol Chem 261:12362–12367
Morales TI, Joyce ME, Sobel ME, Danielpour D, Roberts AB (1991) Transforming growth factor-beta in calf articular cartilage organ cultures: synthesis and distribution. Arch Biochem Biophys 288:397–405
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. J Cell Biol 145:783–794
Yang X, Chen L, Xu X, Li C, Huang C, Deng CX (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 153:35–46
Serra R, Johnson M, Filvaroff EH, LaBorde J, Sheehan DM, Derynck R, Moses HL (1997) Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 139:541–552
Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118:3573–3584
Ornitz DM (2005) FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16:205–213
Henderson JE, Naski MC, Aarts MM, Wang D, Cheng L, Goltzman D, Ornitz DM (2000) Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. J Bone Miner Res 15:155–165
Naski MC, Colvin JS, Coffin JD, Ornitz DM (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development (Camb) 125:4977–4988
Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12:390–397
Murakami S, Balmes G, McKinney S, Zhang Z, Givol D, de Crombrugghe B (2004) Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Genes Dev 18:290–305
Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M et al (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80–86
Liu Z, Lavine KJ, Hung IH, Ornitz DM (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302:80–91
Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (1999) Sox9 is required for cartilage formation. Nat Genet 22:85–89
Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16:2813–2828
Lefebvre V, Li P, de Crombrugghe B (1998) A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J 17:5718–5733
Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B, Lefebvre V (2001) The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell 1:277–290
Saito T, Ikeda T, Nakamura K, Chung UI, Kawaguchi H (2007) S100A1 and S100B, transcriptional targets of SOX trio, inhibit terminal differentiation of chondrocytes. EMBO Rep 8:504–509
Yamashita S, Andoh M, Ueno-Kudoh H, Sato T, Miyaki S, Asahara H (2009) Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes. Exp Cell Res 315:2231–2240
Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, Nakamura K, Kawaguchi H, Ikegawa S, Chung UI (2004) The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis Rheum 50:3561–3573
Hattori T, Muller C, Gebhard S, Bauer E, Pausch F, Schlund B, Bosl MR, Hess A, Surmann-Schmitt C, von der Mark H et al (2010) SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Development (Camb) 137:901–911
Bi W, Huang W, Whitworth DJ, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (2001) Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci USA 98:6698–6703
Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M et al (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764
Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR et al (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771
Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH et al (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779
Fujita T, Azuma Y, Fukuyama R, Hattori Y, Yoshida C, Koida M, Ogita K, Komori T (2004) Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3 K-Akt signaling. J Cell Biol 166:85–95
Higashikawa A, Saito T, Ikeda T, Kamekura S, Kawamura N, Kan A, Oshima Y, Ohba S, Ogata N, Takeshita K et al (2009) Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type X collagen gene. Arthritis Rheum 60:166–178
Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G (2001) Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev 15:467–481
Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M, Ohmori T, Enomoto H, Nakata K, Takada K et al (2001) Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 153:87–100
Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y et al (2004) Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18:952–963
Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH et al (2002) Cbfbeta interacts with Runx2 and has a critical role in bone development. Nat Genet 32:639–644
Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, Satake M, Takada K, Komori T (2002) Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nat Genet 32:633–638
Kang JS, Alliston T, Delston R, Derynck R (2005) Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J 24:2543–2555
Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, McAnally J, Pomajzl C, Shelton JM, Richardson JA et al (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119:555–566
Sun X, Wei L, Chen Q, Terek RM (2009) HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity. J Biol Chem 284:21881–21890
Long F, Chung UI, Ohba S, McMahon J, Kronenberg HM, McMahon AP (2004) Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development (Camb) 131:1309–1318
Nakamura T, Aikawa T, Iwamoto-Enomoto M, Iwamoto M, Higuchi Y, Pacifici M, Kinto N, Yamaguchi A, Noji S, Kurisu K et al (1997) Induction of osteogenic differentiation by hedgehog proteins. Biochem Biophys Res Commun 237:465–469
van der Horst G, Farih-Sips H, Lowik CW, Karperien M (2003) Hedgehog stimulates only osteoblastic differentiation of undifferentiated KS483 cells. Bone (NY) 33:899–910
Rodda SJ, McMahon AP (2006) Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development (Camb) 133:3231–3244
Shimoyama A, Wada M, Ikeda F, Hata K, Matsubara T, Nifuji A, Noda M, Amano K, Yamaguchi A, Nishimura R et al (2007) Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell 18:2411–2418
Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T, Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima T, Kuramochi A et al (2008) Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity. Dev Cell 14:689–699
Joeng KS, Long F (2009) The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization. Development (Camb) 136:4177–4185
Maeda Y, Nakamura E, Nguyen MT, Suva LJ, Swain FL, Razzaque MS, Mackem S, Lanske B (2007) Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc Natl Acad Sci USA 104:6382–6387
Kimura H, Ng JM, Curran T (2008) Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13:249–260
Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523
Rawadi G, Vayssiere B, Dunn F, Baron R, Roman-Roman S (2003) BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res 18:1842–1853
Patel S, Doble B, Woodgett JR (2004) Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword? Biochem Soc Trans 32:803–808
Kugimiya F, Kawaguchi H, Ohba S, Kawamura N, Hirata M, Chikuda H, Azuma Y, Woodgett JR, Nakamura K, Chung UI (2007) GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS One 2:e837
Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development (Camb) 132:49–60
Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738
Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521
Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA 2nd, Hartmann C, Li L, Hwang TH, Brayton CF et al (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314
Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329
Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML et al (2004) Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res 19:2033–2040
Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ, Goad MB, Gaur T, Stein GS, Lian JB, Komm BS (2004) The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol 18:1222–1237
Tu X, Joeng KS, Nakayama KI, Nakayama K, Rajagopal J, Carroll TJ, McMahon AP, Long F (2007) Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation. Dev Cell 12:113–127
Takada I, Mihara M, Suzawa M, Ohtake F, Kobayashi S, Igarashi M, Youn MY, Takeyama K, Nakamura T, Mezaki Y et al (2007) A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol 9:1273–1285
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534
Gazzerro E, Canalis E (2006) Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord 7:51–65
Kugimiya F, Kawaguchi H, Kamekura S, Chikuda H, Ohba S, Yano F, Ogata N, Katagiri T, Harada Y, Azuma Y et al (2005) Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation. J Biol Chem 280:35704–35712
Okamoto M, Murai J, Yoshikawa H, Tsumaki N (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 21:1022–1033
Mishina Y, Starbuck MW, Gentile MA, Fukuda T, Kasparcova V, Seedor JG, Hanks MC, Amling M, Pinero GJ, Harada S et al (2004) Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J Biol Chem 279:27560–27566
Kamiya N, Ye L, Kobayashi T, Lucas DJ, Mochida Y, Yamauchi M, Kronenberg HM, Feng JQ, Mishina Y (2008) Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J Bone Miner Res 23:2007–2017
Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature (Lond) 393:382–386
Honjo T (1996) The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells 1:1–9
Kopan R, Goate A (2000) A common enzyme connects notch signaling and Alzheimer’s disease. Genes Dev 14:2799–2806
Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A (1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 13:2801–2810
Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H et al (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci USA 96:11872–11877
Nofziger D, Miyamoto A, Lyons KM, Weinmaster G (1999) Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts. Development (Camb) 126:1689–1702
Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E (2006) Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem 281:6203–6210
Sciaudone M, Gazzerro E, Priest L, Delany AM, Canalis E (2003) Notch 1 impairs osteoblastic cell differentiation. Endocrinology 144:5631–5639
Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R et al (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14:306–314
Engin F, Yao Z, Yang T, Zhou G, Bertin T, Jiang MM, Chen Y, Wang L, Zheng H, Sutton RE et al (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14:299–305
Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, Shindo H, Yamaguchi A (2005) Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem 280:15842–15848
Tezuka K, Yasuda M, Watanabe N, Morimura N, Kuroda K, Miyatani S, Hozumi N (2002) Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res 17:231–239
McLarren KW, Lo R, Grbavec D, Thirunavukkarasu K, Karsenty G, Stifani S (2000) The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1. J Biol Chem 275:530–538
Shen Q, Christakos S (2005) The vitamin D receptor, Runx2, and the Notch signaling pathway cooperate in the transcriptional regulation of osteopontin. J Biol Chem 280:40589–40598
Zamurovic N, Cappellen D, Rohner D, Susa M (2004) Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J Biol Chem 279:37704–37715
Zhang Y, Lian JB, Stein JL, van Wijnen AJ, Stein GS (2009) The Notch-responsive transcription factor Hes-1 attenuates osteocalcin promoter activity in osteoblastic cells. J Cell Biochem 108:651–659
Zanotti S, Smerdel-Ramoya A, Stadmeyer L, Durant D, Radtke F, Canalis E (2008) Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology 149:3890–3899
Ducy P, Karsenty G (1995) Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene. Mol Cell Biol 15:1858–1869
Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754
Komori T (2002) Runx2, a multifunctional transcription factor in skeletal development. J Cell Biochem 87:1–8
Ohba S, Ikeda T, Kugimiya F, Yano F, Lichtler AC, Nakamura K, Takato T, Kawaguchi H, Chung UI (2007) Identification of a potent combination of osteogenic genes for bone regeneration using embryonic stem (ES) cell-based sensor. FASEB J 21:1777–1787
Kobayashi H, Gao Y, Ueta C, Yamaguchi A, Komori T (2000) Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro. Biochem Biophys Res Commun 273:630–636
Choi JY, Pratap J, Javed A, Zaidi SK, Xing L, Balint E, Dalamangas S, Boyce B, van Wijnen AJ, Lian JB et al (2001) Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development. Proc Natl Acad Sci USA 98:8650–8655
Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G (1999) A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13:1025–1036
Liu W, Toyosawa S, Furuichi T, Kanatani N, Yoshida C, Liu Y, Himeno M, Narai S, Yamaguchi A, Komori T (2001) Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol 155:157–166
Geoffroy V, Kneissel M, Fournier B, Boyde A, Matthias P (2002) High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol 22:6222–6233
Miller J, Horner A, Stacy T, Lowrey C, Lian JB, Stein G, Nuckolls GH, Speck NA (2002) The core-binding factor beta subunit is required for bone formation and hematopoietic maturation. Nat Genet 32:645–649
Kanatani N, Fujita T, Fukuyama R, Liu W, Yoshida CA, Moriishi T, Yamana K, Miyazaki T, Toyosawa S, Komori T (2006) Cbf beta regulates Runx2 function isoform-dependently in postnatal bone development. Dev Biol 296:48–61
Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA et al (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309:1074–1078
Dobreva G, Chahrour M, Dautzenberg M, Chirivella L, Kanzler B, Farinas I, Karsenty G, Grosschedl R (2006) SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell 125:971–986
Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN et al (2004) A twist code determines the onset of osteoblast differentiation. Dev Cell 6:423–435
el Ghouzzi V, Le Merrer M, Perrin-Schmitt F, Lajeunie E, Benit P, Renier D, Bourgeois P, Bolcato-Bellemin AL, Munnich A, Bonaventure J (1997) Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet 15:42–46
Howard TD, Paznekas WA, Green ED, Chiang LC, Ma N, Ortiz de Luna RI, Garcia Delgado C, Gonzalez-Ramos M, Kline AD, Jabs EW (1997) Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat Genet 15:36–41
Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ, Glimcher LH (2006) Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. Science 312:1223–1227
Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D (2003) E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 278:27939–27944
Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y, Zhai Y, Irwin DM, Shi Y, Chen D et al (2008) CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation. J Cell Biol 181:959–972
Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Taniguchi T, Takayanagi H (2003) Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev 17:1979–1991
Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29
Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, Takayanagi H (2005) NFAT and Osterix cooperatively regulate bone formation. Nat Med 11:880–885
Wang X, Kua HY, Hu Y, Guo K, Zeng Q, Wu Q, Ng HH, Karsenty G, de Crombrugghe B, Yeh J et al (2006) p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling. J Cell Biol 172:115–125
Author information
Authors and Affiliations
Corresponding author
Additional information
U. Chung is a recipient of the JSBMR Distinguished Scientist Award of 2009.
About this article
Cite this article
Hojo, H., Ohba, S., Yano, F. et al. Coordination of chondrogenesis and osteogenesis by hypertrophic chondrocytes in endochondral bone development. J Bone Miner Metab 28, 489–502 (2010). https://doi.org/10.1007/s00774-010-0199-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00774-010-0199-7