Minireview: Transcriptional Regulation in Development of Bone

Tatsuya Kobayashi and Henry Kronenberg Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 Downloaded from https://academic.oup.com/endo/article/146/3/1012/2499970 by guest on 25 September 2021

Regulation of gene expression by transcription factors is one distinct developmental programs. These cells go through mul- of the major mechanisms for controlling cellular functions. tiple differentiation stages, which are often regulated by spe- Recent advances in genetic manipulation of model animals cific transcription factors. In this minireview, we will discuss has allowed the study of the roles of various genes and their selected transcription factors that have been demonstrated to products in physiological settings and has demonstrated the critically affect bone cell development. Further study of these importance of specific transcription factors in bone develop- molecules will lead to deeper understanding in mechanisms that ment. Three lineages of bone cells, chondrocytes, osteoblasts, govern development of bone. (Endocrinology 146: 1012–1017, and osteoclasts, develop and differentiate according to their 2005)

ONE DEVELOPMENT IS achieved through the use of signaling (4), likely play an important role. After the formation B two distinct pathways, intramembranous and endo- of mesenchymal condensations, cells start proliferating again chondral bone formation. In intramembranous bone for- and differentiate into chondrocytes (Fig. 1). mation, mesenchymal cells condense and directly differentiate into bone-forming osteoblasts. In contrast, in Sox9 (sex reversal Y-related high-mobility group box endochondral bone formation, mesenchymal cells con- protein) and chondrocyte commitment dense and then become chondrocytes. This cartilage mold then directs the formation of osteoblasts, which form ma- Analysis of genetically manipulated mice demonstrated that ture bone. This bone is continually remodeled by cycles of Sox transcription factors, members of the high mobility group bone formation and resorption. Osteoclasts, of hemato- superfamily, are necessary for conversion of condensed mes- poietic origin, are responsible for bone resorption. Thus, enchymal cells to chondrocytes. Studies of chimeric mice (5) three distinct cell types (chondrocytes, osteoblasts, and and conditional knockouts (6) have shown that Sox9 is required osteoclasts) from two cell lineages direct the formation and for formation of normal mesenchymal condensations, for con- remodeling of bone (1). version of mesenchymal cells to chondrocytes, for proliferation of chondrocytes, and for suppression of premature conversion Endochondral Bone Formation and Chondrocyte of these chondrocytes to hypertrophic chondrocytes. Sox9 is Differentiation also required for the production of L-Sox5 and Sox6, two related Sox family members required for normal chondrocyte function Formation of the cartilage anlage starts with mesen- (7). Sox9 is not only required for development of chondrocytes chymal condensation (2). The molecular mechanism that but also directly regulates expression of genes important for regulates this process at the transcriptional level is not fully chondrocyte function, such as Col2a1 (8), Col11a2 (9), Agc1 understood. However, because bone morphogenetic protein (aggrecan) (10), and Mia (Cdrap) (11). The function of Sox9 may (BMP) signaling appears crucial for this process (3), Smads be modulated by phosphorylation by the PTH-related peptide [a name derived from Sma and MADD (Mother against signaling pathway (12). It is, therefore, possible that Sox9 decapentaplegic)], transcription factors downstream of BMP mediates part of PTH-related peptide action to regulate hypertrophic differentiation. First Published Online December 16, 2004 Expression of Sox9 begins in the mesenchymal condensation. Abbreviations: BMP, Bone morphogenetic protein; FGF, fibroblast BMPs can induce SOX9 expression, and noggin, a BMP antag- growth factor; Ihh, Indian hedgehog; LEF, lymphoid enhancer-binding onist, blocks expression of SOX9 in mesenchymal condensa- factor; M-CSF, macrophage colony-stimulating factor; MITF, microph- tions (13). Cytokines such as IL-1 and TNF-␣, and nuclear factor thalmia-associated transcription factors; NFATc1 nuclear factor of ac- ␬ ␬ tivated T cells, cytoplasmic, calcineurin-dependent 1; NF-␬B, nuclear B (NF- B), the transcription factor that mediates many actions factor ␬B; Osx, Osterix; RANK, receptor activator of nuclear factor ␬B; of these cytokines, suppress Sox9 expression, partly through RANKL, RANK ligand; Smad, a name derived from Sma and MADD induction of posttranscriptional mRNA degradation (14, 15); (Mother against decapentaplegic); Sox, sex reversal Y-related high- this suppression of SOX9 probably contributes to chondrocyte mobility group box protein; TCF, T-cell factor; TFE, transcription factor E; Wnt, a name that combines wingless and int. loss in inflammatory arthritis. How specific transcription fac- Endocrinology is published monthly by The Endocrine Society (http:// tors regulate Sox9 gene transcription is a central question, al- www.endo-society.org), the foremost professional society serving the though it appears complicated; genetic analysis of human and endocrine community. mouse Sox9 mutations demonstrated that cis elements quite

1012 Kobayashi and Kronenberg • Minireview Endocrinology, March 2005, 146(3):1012–1017 1013 Downloaded from https://academic.oup.com/endo/article/146/3/1012/2499970 by guest on 25 September 2021

FIG. 1. Differentiation of bone cells of three lineages and its regulation by transcription factors. Transcription factors important for bone cell differentiation are indicated by bold black letters with arrows at major differentiation steps. Signaling molecules are indicated by blue letters. Osteoblasts and chondrocytes are derived from common mesenchymal precursors. During endochondral bone formation, mesenchymal cells condense and differentiate into chondrocytes. BMP signaling is likely required for these processes. Sox9 and its related molecules L-Sox5 and Sox6 play a pivotal role in commitment and maintenance of chondrocyte phenotypes. In the growth plate, chondrocytes proliferate and further differentiate into column-forming cells, then into postmitotic hypertrophic chondrocytes. Runx2 expression stimulates terminal differentiation. Runx2 and Osx are both required for osteoblast differentiation. Runx2 expression starts before that of Osx. Its activity is regulated by interaction with other transcription factors such as members of the Twist family. Osteoclasts differentiate from hematopoietic lineage cells through multiple steps. M-CSF and RANLK are essential external stimuli for osteoclastogenesis. PU.1, MITFs, Nf-␬B, Fos/Fra1, and NFATc1 are all required for differentiation of mature osteoclasts. distant from the transcription start site of the Sox9 gene are become hypertrophic. Runx transcription factors are mem- critical for Sox9 transcription in cartilage (16). bers of the runt family, named for the DNA binding domain, Interestingly, overexpression of Sox9 in the cartilage conserved across species from Drosophila to humans (22). causes a decrease in chondrocyte proliferation and a delay in Mice missing Runx2 show a defect in chondrocyte matura- bone development. This decrease in proliferation may result tion, with lack of hypertrophic chondrocytes in many bones from binding of Sox9 to ␤-catenin, the essential component (23), and mice missing both Runx2 and Runx3 completely of the canonical Wnt (a name that combines wingless and int) lack chondrocytes (24). Furthermore, overexpression of signaling pathway (17). Some Wnt members are expressed in Runx2 hastens hypertrophy and even converts chondrocytes cartilage, and effects of Wnt signaling in cartilage have been in the trachea, which normally never hypertrophy, into hy- demonstrated (18–21). Along with the observation that over- pertrophic chondrocytes and then bone (25, 26). activation or deletion of ␤-catenin in chondrocytes resulted The stages of chondrocyte differentiation are regulated by a in severe skeletal dysplasias, these findings suggest that the complex series of signaling molecules and transcription factors transcription complex, lymphoid enhancer-binding factor in addition to Sox9 and Runx2/3. Differentiation of early peri- ␤ (LEF)/T-cell factor (TCF)/ -catenin, regulates some aspects articular chondrocytes into flat, columnar proliferating chon- of cartilage development (17). drocytes appears to be regulated by multiple signaling molecules such as Indian hedgehog (Ihh) and Wnts (19, 27). It is, Runx2 and chondrocyte hypertrophy therefore, likely that some of the downstream transcription Chondrocytes divide and produce a characteristic matrix factors triggered by Ihh and wnts, Gli family members, and the but then stop dividing, change the matrix they synthesize, ␤-catenin/TCF/LEF complex, play a role in this step. Chon- and become quite large (hypertrophic). Runx2 and, to a lesser drocyte differentiation is accompanied by changes in prolifer- extent, Runx3, are the major transcription factors controlling ation. Alterations in fibroblast growth factor (FGF) signaling the crucial steps because chondrocytes stop dividing and (28, 29), BMP signaling (30), and Ihh signaling (31–33) partic- 1014 Endocrinology, March 2005, 146(3):1012–1017 Kobayashi and Kronenberg • Minireview ipate in regulating chondrocyte proliferation. The suppressive osteoblastic differentiation and function. These include ac- effect of fibroblast growth factor signaling on proliferation is tivator protein-1 and its related molecules (62), Dlx5 (63, 64), regulated by signal transducer and activator of transcription-1 Msx1 (65), Msx2 (66–68), Twist (69), Atf4 (70), and nuclear at the transcriptional level (34). Overexpression of Ihh is asso- steroid hormone receptors such as androgen receptors (71) ciated with an increase in cyclin D1 expression (33), which and estrogen receptors (72). ultimately stimulates cell cycle progression by activating E2F transcription factors (35). BMP signaling, therefore, involving Osteoclast Differentiation Smad 1, 5, and 8 transcription factors, generally stimulates hypertrophic differentiation (30, 36–39). Misexpression of a Osteoclasts develop from monocytic precursors of the he- homeobox-containing transcription factor, Dlx5, which is nor- matopoietic lineage. Analysis of a variety of mutant mice mally expressed in the prehypertrophic region of the growth with osteopetrosis, caused by loss or impairment of oste- plate, stimulates hypertrophic differentiation in developing oclast function, has provided valuable insights into the ge- Downloaded from https://academic.oup.com/endo/article/146/3/1012/2499970 by guest on 25 September 2021 chicken limbs (40). Considering that Dlx5 is downstream of netic basis for osteoclast differentiation. The Ets family tran- BMP signaling in several other cell types, Dlx5 and its related scription factor, PU.1, is responsible for the earliest molecule, Dlx6 (41), may mediate BMP action regulating hy- established event in osteoclastogenesis. PU.1 null mice lack pertrophic differentiation. These animal models with Dlx mod- not only osteoclasts but also macrophages, while preserving ulation, however, need cautious interpretation because neither the ability to produce early monocytic cells (73). After com- misexpression nor deletion of the genes is chondrocyte specific. mitment to the osteoclast lineage, mononuclear cells respond to macrophage colony-stimulating factor (M-CSF), produced by nearby stromal cells, through activation of c-fms, the Osteoblast Differentiation receptor for M-CSF; mice with inactivating mutations of M- Two transcription factors, Runx2 containing a runt domain CSF form macrophages normally, but lack osteoclasts (74). (42, 43) and Osterix (Osx; SP7) with a zinc-finger motif (44) The other signaling system essential for osteoclast differen- are absolutely required for osteoblast differentiation during tiation is triggered when RANKL [receptor activator of nu- both intramembranous and endochondral bone formation. clear factor ␬B (RANK) ligand], a member of the TNF family, Analysis of Osx null mice shows that Osx is genetically activates its receptor RANK, a member of the TNF receptor downstream of Runx2. Runx2 is expressed in the lateral family. Several transcription factors have been found crucial mesoderm, mesenchymal condensations, and chondrocytes for osteoclast differentiation downstream of M-CSF/c-fms in addition to osteoblasts. Both overexpression of Runx2 and and RANKL/RANK signaling. Microphthalmia-associated expression of a dominant-negative form of Runx2 in osteo- transcription factors (MITF), transcription factor E (TFE3), blasts impairs bone formation, suggesting that regulation of TFEB, TFEC, and MITF, are essential for differentiation of different stages of osteoblast differentiation by Runx2 is com- mononuclear precursors into multinucleated osteoclasts (75). plex (45, 46). Runx2 is regulated by phosphorylation and also The phenotypic variance among different mutations in the interacts with other transcription factors, such as Smads 1 MITF gene and analysis of compound mutants for mitf and and 5 (47, 48), Smad 3 (49), signal transducer and activator tfe3 demonstrated that these family members have redun- of transcription-1 (50), Menin (51), Hey1 (52), Grg5 (53) p300 dant roles (76). MITF directly regulates genes important for (54), and Twists (55). Runx2 target genes include genes ex- osteoclast function such as tartrate-resistant acid phospha- pressed by mature osteoblasts, such as osteocalcin, bone tase (TRAP) (77, 78), cathepsin K (79), and osteoclast-asso- sialoprotein, osteopontin, and collagen ␣1(I) (22). ciated receptor (OSCAR) (80) and also may regulate other Little is known about how Osx regulates osteoblast differ- transcription factors essential for osteoclastogenesis, such as entiation and function. Expression of genes characteristic of PU.1 and c-Fos, by physical interaction (77, 81). The impor- mature osteoblasts is absent in cells surrounding chondrocytes tance of NF-␬B was demonstrated by that the absence of in Osx null mice, and instead these cells express genes char- multinucleated bone-resorbing cells in NF-␬B mutant mice acteristic of chondrocytes. Thus, Osx may be important for (82). Development of macrophages is preserved in NF-␬B directing precursor cells away from the chondrocyte lineage null mice, suggesting that NF-␬B functions later than PU.1 and toward the osteoblast lineage (44). Recently, an important during osteoclast differentiation. In addition to NF-␬B, the role in osteoblast development for ␤-catenin has become clear. RANK signaling pathway activates at least two other tran- ␤-Catenin is the downstream mediator of canonical Wnt sig- scription factors essential for osteoclast differentiation: c-fos, naling that forms a transcription-regulating complex with a member of the activator protein-1 family of transcription TCF/LEF transcription factors. Inactivating mutations of LRP5 factors, and NFATc1 (nuclear factor of activated T cells, cy- (low-density lipoprotein receptor-related protein 5), which en- toplasmic, calcineurin-dependent 1). The absence of c-fos codes a Wnt coreceptor required for activation of canonical Wnt causes severe osteopetrosis with lack of osteoclasts (83, 84). signaling, cause osteoporosis in humans (56) and in mice (57), This defect is rescued by expression of a Fos-related molecule whereas other mutations in LRP5 cause high bone mass (58, 59). Fra1that lacks a transactivation domain; this suggests that Recent work in which ␤-catenin is conditionally knocked out Fos regulates osteoclast formation by interacting with other from cells at various stages of the osteoblast lineage, suggests DNA binding molecules (85). C-fos is required for the initial that ␤-catenin plays multiple critical roles in osteoblast differ- induction of NFATc1 expression (86, 87). NFATc1, identified entiation (60, 61). as a gene up-regulated in RANKL-stimulated bone marrow- Alterations in functions of various other non-bone-specific derived monocyte/macrophage precursor cells (88, 89), transcription factors have been also demonstrated to affect plays a critical role in osteoclast differentiation (90). Unlike Kobayashi and Kronenberg • Minireview Endocrinology, March 2005, 146(3):1012–1017 1015 wild-type ES cells, ES cells missing the NFATc1 gene are not of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proc Natl Acad Sci USA 95:10649–10654 able to differentiate into osteoclasts in vitro. Furthermore, 17. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng overexpression of a constitutively active form of NFATc1 in JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe c-fos null cells restores expression of osteoclast-specific B 2004 Interactions between Sox9 and ␤-catenin control chondrocyte differentiation. Genes Dev 18:1072–1087 genes, demonstrating that NFATc1 is a critical transcrip- 18. Guo X, Day TF, Jiang X, Garrett-Beal L, Topol L, Yang Y 2004 Wnt/␤-catenin tional regulator downstream of c-fos during osteoclast dif- signaling is sufficient and necessary for synovial joint formation. Genes Dev ferentiation (87). 18:2404–2417 19. Yang Y, Topol L, Lee H, Wu J 2003 Wnt5a and Wnt5b exhibit distinct activities We have briefly discussed transcription factors that have in coordinating chondrocyte proliferation and differentiation. Development been shown through genetic studies to be important in bone 130:1003–1015 development (see Fig. 1 for a summary of these transcription 20. Hartmann C, Tabin CJ 2000 Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127:3141–3159 factors and critical signaling systems). Although animal 21. Yamaguchi TP, Bradley A, McMahon AP, Jones S 1999 A Wnt5a pathway models with genetic alterations demonstrate the physiolog- underlies outgrowth of multiple structures in the vertebrate embryo. Devel- Downloaded from https://academic.oup.com/endo/article/146/3/1012/2499970 by guest on 25 September 2021 ical importance of genes, such models often give limited opment 126:1211–1223 22. Ducy P 2000 Cbfa1: a molecular switch in osteoblast biology. Dev Dyn 219: information about the primary targets of these transcription 461–471 factors and subsequent cascades of gene expression. There- 23. Inada M, Yasui T, Nomura S, Miyake S, Deguchi K, Himeno M, Sato M, fore, the precise way that these transcription factors regulate Yamagiwa H, Kimura T, Yasui N, Ochi T, Endo N, Kitamura Y, Kishimoto T, Komori T 1999 Maturational disturbance of chondrocytes in Cbfa1-deficient bone cell development and function in vivo is limited and an mice. Dev Dyn 214:279–290 important agenda for the future. 24. Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, Komori T 2004 Runx2 and Runx3 are essential for chondrocyte maturation, Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18:952–963 Acknowledgments 25. Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M, Ohmori T, Enomoto H, Nakata K, Takada K, Kurisu K, Komori T 2001 Received October 13, 2004. Accepted November 9, 2004. Skeletal malformations caused by overexpression of Cbfa1 or its dominant Address all correspondence and requests for reprints to: Henry Kro- negative form in chondrocytes. J Cell Biol 153:87–100 26. Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G 2001 Continuous nenberg, Endocrine Unit, Department of Medicine, Massachusetts Gen- expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to eral Hospital, Boston, Massachusetts 02114. induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1- deficient mice. Genes Dev 15:467–481 27. Kobayashi T, Chung UI, Schipani E, Starbuck M, Karsenty G, Katagiri T, References Goad DL, Lanske B, Kronenberg HM 2002 PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. Devel- 1. Karsenty G, Wagner EF 2002 Reaching a genetic and molecular understanding opment 129:2977–2986 of skeletal development. Dev Cell 2:389–406 28. Ornitz DM, Marie PJ 2002 FGF signaling pathways in endochondral and 2. Hall BK, Miyake T 2000 All for one and one for all: condensations and the intramembranous bone development and human genetic disease. Genes Dev initiation of skeletal development. Bioessays 22:138–147 16:1446–1465 3. Pizette S, Niswander L 2000 BMPs are required at two steps of limb chon- 29. Iwata T, Li CL, Deng CX, Francomano CA 2001 Highly activated Fgfr3 with drogenesis: formation of prechondrogenic condensations and their differen- the K644M mutation causes prolonged survival in severe dwarf mice. Hum tiation into chondrocytes. Dev Biol 219:237–249 Mol Genet 10:1255–1264 4. Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K 2002 Two major ␤ 30. Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Smad pathways in TGF- superfamily signalling. Genes Cells 7:1191–1204 Vortkamp A 2001 BMP and Ihh/PTHrP signaling interact to coordinate chon- Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B 5. 1999 Sox9 is drocyte proliferation and differentiation. Development 128:4523–4534 required for cartilage formation. Nat Genet 22:85–89 31. St-Jacques B, Hammerschmidt M, McMahon AP 1999 Indian hedgehog sig- 6. Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B 2002 naling regulates proliferation and differentiation of chondrocytes and is es- The transcription factor Sox9 has essential roles in successive steps of the sential for bone formation. Genes Dev 13:2072–2086 chondrocyte differentiation pathway and is required for expression of Sox5 32. Karp SJ, Schipani E, St-Jacques B, Hunzelman J, Kronenberg H, McMahon and Sox6. Genes Dev 16:2813–2828 AP 2000 Indian hedgehog coordinates endochondral bone growth and mor- 7. Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer RR, de Crombrugghe phogenesis via parathyroid hormone related-protein-dependent and -inde- B, Lefebvre V 2001 The transcription factors L-Sox5 and Sox6 are essential for pendent pathways. Development 127:543–548 cartilage formation. Dev Cell 1:277–290 8. Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B 1997 33. Long F, Zhang XM, Karp S, Yang Y, McMahon AP 2001 Genetic manipulation SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro ␣1(II) of hedgehog signaling in the endochondral skeleton reveals a direct role in the collagen gene. Mol Cell Biol 17:2336–2346 regulation of chondrocyte proliferation. Development 128:5099–5108 9. Bridgewater LC, Lefebvre V, de Crombrugghe B 1998 Chondrocyte-specific 34. Sahni M, Ambrosetti DC, Mansukhani A, Gertner R, Levy D, Basilico C 1999 enhancer elements in the Col11a2 gene resemble the Col2a1 tissue-specific FGF signaling inhibits chondrocyte proliferation and regulates bone devel- enhancer. J Biol Chem 273:14998–15006 opment through the STAT-1 pathway. Genes Dev 13:1361–1366 10. Sekiya I, Tsuji K, Koopman P, Watanabe H, Yamada Y, Shinomiya K, Nifuji 35. Coqueret O 2002 Linking cyclins to transcriptional control. Gene 299:35–55 A, Noda M 2000 SOX9 enhances aggrecan gene promoter/enhancer activity 36. De Luca F, Barnes KM, Uyeda JA, De-Levi S, Abad V, Palese T, Mericq V, and is up-regulated by retinoic acid in a cartilage-derived cell line, TC6. J Biol Baron J 2001 Regulation of growth plate chondrogenesis by bone morphoge- Chem 275:10738–10744 netic protein-2. Endocrinology 142:430–436 11. Xie WF, Zhang X, Sakano S, Lefebvre V, Sandell LJ 1999 Trans-activation of 37. Tsumaki N, Nakase T, Miyaji T, Kakiuchi M, Kimura T, Ochi T, Yoshikawa the mouse cartilage-derived retinoic acid-sensitive protein gene by Sox9. J Bone H 2002 Bone morphogenetic protein signals are required for cartilage forma- Miner Res 14:757–763 tion and differently regulate joint development during skeletogenesis. J Bone 12. Huang W, Chung UI, Kronenberg HM, de Crombrugghe B 2001 The chon- Miner Res 17:898–906 drogenic transcription factor Sox9 is a target of signaling by the parathyroid 38. Tsumaki N, Tanaka K, Arikawa-Hirasawa E, Nakase T, Kimura T, Thomas hormone-related peptide in the growth plate of endochondral bones. Proc Natl JT, Ochi T, Luyten FP, Yamada Y 1999 Role of CDMP-1 in skeletal morpho- Acad Sci USA 98:160–165 genesis: promotion of mesenchymal cell recruitment and chondrocyte differ- 13. Healy C, Uwanogho D, Sharpe PT 1999 Regulation and role of Sox9 in entiation. J Cell Biol 144:161–173 cartilage formation. Dev Dyn 215:69–78 39. Grimsrud CD, Romano PR, D’Souza M, Puzas JE, Reynolds PR, Rosier RN, 14. Murakami S, Lefebvre V, de Crombrugghe B 2000 Potent inhibition of the O’Keefe RJ 1999 BMP-6 is an autocrine stimulator of chondrocyte differen- master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis tiation. J Bone Miner Res 14:475–482 factor-␣. J Biol Chem 275:3687–3692 40. Ferrari D, Kosher RA 2002 Dlx5 is a positive regulator of chondrocyte dif- 15. Sitcheran R, Cogswell PC, Baldwin Jr AS 2003 NF-␬B mediates inhibition of ferentiation during endochondral ossification. Dev Biol 252:257–270 mesenchymal cell differentiation through a posttranscriptional gene silencing 41. Robledo RF, Rajan L, Li X, Lufkin T 2002 The Dlx5 and Dlx6 homeobox genes mechanism. Genes Dev 17:2368–2373 are essential for craniofacial, axial, and appendicular skeletal development. 16. Wunderle VM, Critcher R, Hastie N, Goodfellow PN, Schedl A 1998 Deletion Genes Dev 16:1089–1101 1016 Endocrinology, March 2005, 146(3):1012–1017 Kobayashi and Kronenberg • Minireview

42. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, 62. Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ 1997 Mukhopadhyay K, Ford K, Nestler EJ, Baron R 2000 Overexpression of ⌬FosB Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for transcription factor(s) increases bone formation and inhibits adipogenesis. Nat osteoblast differentiation and bone development. Cell 89:765–771 Med 6:985–990 43. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu 63. Acampora D, Merlo GR, Paleari L, Zerega B, Postiglione MP, Mantero S, Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki Bober E, Barbieri O, Simeone A, Levi G 1999 Craniofacial, vestibular and bone S, Kishimoto T 1997 Targeted disruption of Cbfa1 results in a complete lack defects in mice lacking the Distal-less-related gene Dlx5. Development 126: of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764 3795–3809 44. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de 64. Miyama K, Yamada G, Yamamoto TS, Takagi C, Miyado K, Sakai M, Ueno Crombrugghe B 2002 The novel zinc finger-containing transcription factor N, Shibuya H 1999 A BMP-inducible gene, dlx5, regulates osteoblast differ- osterix is required for osteoblast differentiation and bone formation. Cell entiation and mesoderm induction. Dev Biol 208:123–133 108:17–29 65. Satokata I, Maas R 1994 Msx1 deficient mice exhibit cleft palate and abnor- 45. Liu W, Toyosawa S, Furuichi T, Kanatani N, Yoshida C, Liu Y, Himeno M, malities of craniofacial and tooth development. Nat Genet 6:348–356 Narai S, Yamaguchi A, Komori T 2001 Overexpression of Cbfa1 in osteoblasts 66. Liu YH, Tang Z, Kundu RK, Wu L, Luo W, Zhu D, Sangiorgi F, Snead ML, inhibits osteoblast maturation and causes osteopenia with multiple fractures. Maxson RE 1999 Msx2 gene dosage influences the number of proliferative J Cell Biol 155:157–166 osteogenic cells in growth centers of the developing murine skull: a possible Downloaded from https://academic.oup.com/endo/article/146/3/1012/2499970 by guest on 25 September 2021 46. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, mechanism for MSX2-mediated craniosynostosis in humans. Dev Biol 205: Karsenty G 1999 A Cbfa1-dependent genetic pathway controls bone formation 260–274 beyond embryonic development. Genes Dev 13:1025–1036 67. Liu YH, Kundu R, Wu L, Luo W, Ignelzi Jr MA, Snead ML Maxson Jr RE 47. Lee KS, Hong SH, Bae SC 2002 Both the Smad and p38 MAPK pathways play 1995 Premature suture closure and ectopic cranial bone in mice expressing a crucial role in Runx2 expression following induction by transforming growth Msx2 transgenes in the developing skull. Proc Natl Acad Sci USA 92: factor-␤ and bone morphogenetic protein. Oncogene 21:7156–7163 6137–6141 48. Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, 68. Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, Maeda T, Takano Miyazono K, Ito Y 2000 A RUNX2/PEBP2␣ A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Y, Uchiyama M, Heaney S, Peters H, Tang Z, Maxson R, Maas R 2000 Msx2 Natl Acad Sci USA 97:10549–10554 deficiency in mice causes pleiotropic defects in bone growth and ectodermal 49. Alliston T, Choy L, Ducy P, Karsenty G, Derynck R 2001 TGF-␤-induced organ formation. Nat Genet 24:391–395 repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and 69. Rose CS, Malcolm S 1997 A TWIST in development. Trends Genet 13:384–387 inhibits osteoblast differentiation. EMBO J 20:2254–2272 70. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, 50. Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Tan- Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G 2004 iguchi T, Takayanagi H 2003 Stat1 functions as a cytoplasmic attenuator of ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev implication for Coffin-Lowry syndrome. Cell 117:387–398 17:1979–1991 71. Yeh S, Tsai MY, Xu Q, Mu XM, Lardy H, Huang KE, Lin H, Yeh SD, 51. Sowa H, Kaji H, Hendy GN, Canaff L, Komori T, Sugimoto T, Chihara K 2004 Altuwaijri S, Zhou X, Xing L, Boyce BF, Hung MC, Zhang S, Gan L, Chang Menin is required for BMP-2-and TGF-␤-regulated osteoblastic differentiation C, Hung MC 2002 Generation and characterization of androgen receptor through interaction with Smads and Runx2. J Biol Chem 279:40267–40275 knockout (ARKO) mice: an in vivo model for the study of androgen functions 52. Zamurovic N, Cappellen D, Rohner D, Susa M 2004 Coordinated activation in selective tissues. Proc Natl Acad Sci USA 99:13498–13503 of Notch, Wnt and TGF-␤ signaling pathways in BMP-2 induced osteogenesis: 72. Sims NA, Clement-Lacroix P, Minet D, Fraslon-Vanhulle C, Gaillard-Kelly notch target gene Hey1 inhibits mineralization and Runx2 transcriptional M, Resche-Rigon M, Baron R 2003 A functional androgen receptor is not activity. J Biol Chem 279:37704–37715 sufficient to allow estradiol to protect bone after gonadectomy in estradiol 53. Wang W, Wang YG, Reginato AM, Glotzer DJ, Fukai N, Plotkina S, Karsenty receptor-deficient mice. J Clin Invest 111:1319–1327 G, Olsen BR 2004 Groucho homologue Grg5 interacts with the transcription 73. Tondravi MM, McKercher SR, Anderson K, Erdmann JM, Quiroz M, Maki factor Runx2-Cbfa1 and modulates its activity during postnatal growth in R, Teitelbaum SL 1997 Osteopetrosis in mice lacking haematopoietic tran- mice. Dev Biol 270:364–381 scription factor PU.1. Nature 386:81–84 54. Sierra J, Villagra A, Paredes R, Cruzat F, Gutierrez S, Javed A, Arriagada G, 74. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Olate J, Imschenetzky M, Van Wijnen AJ, Lian JB, Stein GS, Stein JL, Sudo T, Shultz LD 1990 The murine mutation osteopetrosis is in the coding Montecino M 2003 Regulation of the bone-specific osteocalcin gene by p300 region of the macrophage colony stimulating factor gene. Nature 345: requires Runx2/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic 442–444 histone acetyltransferase activity. Mol Cell Biol 23:3339–3351 75. Hershey CL, Fisher DE 2004 Mitf and Tfe3: members of a b-HLH-ZIP tran- 55. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz scription factor family essential for osteoclast development and function. Bone DM, Olson EN, Justice MJ, Karsenty G 2004 A twist code determines the onset 34:689–696 of osteoblast differentiation. Dev Cell 6:423–435 76. Steingrimsson E, Tessarollo L, Pathak B, Hou L, Arnheiter H, Copeland NG, 56. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang Jenkins NA 2002 Mitf and Tfe3, two members of the Mitf-Tfe family of H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi bHLH-Zip transcription factors, have important but functionally redundant W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner roles in osteoclast development. Proc Natl Acad Sci USA 99:4477–4482 M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, et al 2001 LDL 77. Partington GA, Fuller K, Chambers TJ, Pondel M 2004 Mitf-PU.1 interactions receptor-related protein 5 (LRP5) affects bone accrual and eye development. with the tartrate-resistant acid phosphatase gene promoter during osteoclast Cell 107:513–523 differentiation. Bone 34:237–245 57. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass 2nd DA, Hart- 78. Luchin A, Purdom G, Murphy K, Clark MY, Angel N, Cassady AI, Hume DA, mann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L 2002 Ostrowski MC 2000 The microphthalmia transcription factor regulates ex- Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and per- pression of the tartrate-resistant acid phosphatase gene during terminal dif- sistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt core- ferentiation of osteoclasts. J Bone Miner Res 15:451–460 ceptor. J Cell Biol 157:303–314 Motyckova G, Weilbaecher KN, Horstmann M, Rieman DJ, Fisher DZ, 58. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning 79. SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braun- Fisher DE 2001 Linking osteopetrosis and pycnodysostosis: regulation of ca- schweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig thepsin K expression by the microphthalmia transcription factor family. Proc C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, et al. 2002 A mutation Natl Acad Sci USA 98:5798–5803 in the LDL receptor-related protein 5 gene results in the autosomal dominant 80. So H, Rho J, Jeong D, Park R, Fisher DE, Ostrowski MC, Choi Y, Kim N 2003 high-bone-mass trait. Am J Hum Genet 70:11–19 Microphthalmia transcription factor and PU.1 synergistically induce the leu- 59. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, kocyte receptor osteoclast-associated receptor gene expression. J Biol Chem Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Boller- 278:24209–24216 slev J, Van Hul W 2003 Six novel missense mutations in the LDL receptor- 81. Sato M, Morii E, Takebayashi-Suzuki K, Yasui N, Ochi T, Kitamura Y, related protein 5 (LRP5) gene in different conditions with an increased bone Nomura S 1999 Microphthalmia-associated transcription factor interacts with density. Am J Hum Genet 72:763–771 PU.1 and c-Fos: determination of their subcellular localization. Biochem Bio- 60. Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F 2005 Sequential roles of phys Res Commun 254:384–387 Hedgehog and Wnt signaling in osteoblast development. Development 132: 82. Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi 49–60 A, Tran T, Boyce BF, Siebenlist U 1997 Requirement for NF-␬B in osteoclast 61. Glass D, P.M, Long F, Taketo MM, McMahon AP, Karsenty G 2003 and B-cell development. Genes Dev 11:3482–3496 Regulation of bone formation by wnt signaling. J Bone Miner Res 18:S14 83. Johnson RS, Spiegelman BM, Papaioannou V 1992 Pleiotropic effects of a null (Abstract) mutation in the c-fos proto-oncogene. Cell 71:577–586 Kobayashi and Kronenberg • Minireview Endocrinology, March 2005, 146(3):1012–1017 1017

84. Wang ZQ, Ovitt C, Grigoriadis AE, Mohle-Steinlein U, Ruther U, Wagner M 2002 Transcriptional program of mouse osteoclast differentiation governed EF 1992 Bone and haematopoietic defects in mice lacking c-fos. Nature 360: by the macrophage colony-stimulating factor and the ligand for the receptor 741–745 activator of NF␬ B. J Biol Chem 277:21971–21982 85. Fleischmann A, Hafezi F, Elliott C, Reme CE, Ruther U, Wagner EF 2000 Fra-1 89. Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y, Ku- replaces c-Fos-dependent functions in mice. Genes Dev 14:2695–2700 megawa M, Kimura T, Takeya T 2002 Large scale gene expression analysis of 86. Rao A, Luo C, Hogan P.G 1997 Transcription factors of the NFAT family: osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol regulation and function. Annu Rev Immunol 15:707–747 Chem 277:41147–41156 87. Matsuo K, Galson DL, Zhao C, Peng L, Laplace C, Wang KZ, Bachler MA, 90. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Amano H, Aburatani H, Ishikawa H, Wagner EF 2004 Nuclear factor of Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c- 2002 Induction and activation of the transcription factor NFATc1 (NFAT2) Fos. J Biol Chem 279:26475–26480 integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 88. Cappellen D, Luong-Nguyen NH, Bongiovanni S, Grenet O, Wanke C, Susa 3:889–901

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