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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.05.499 Byline: S.J. Choi (a), I.S. Song (b), J.Q. Feng (c), T. Gao (c), N. Haruyama (d), P. Gautam (a), P.G. Robey (a), Thomas C. Hart (a) Keywords: DLX3; Transgenic mouse; Dentin mineralization; Taurodontism, TDO, odontoblast polarization, apoptosis, TBC1D19 Abbreviations: DLX3, distal less 3; A[micro]CT, microcomputed tomography; TDO, tricho-dento-osseous; Col1A1, collagen type1, alpha-1; DSPP, dentin sialophosphoprotein; Bgn, biglycan; Dcn, decorin; Runx2, runt-related transcription factor 2; Wnt10A, wingless-type MMTV integration site family, member 10A; TBC1D19, Tre-2/Bub2/Cdc16 (TBC)1 domain family, member 19; SEM, scanning electron microscopy Abstract: Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of Runx2, Wnt 10A, and TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism. In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology. Author Affiliation: (a) Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA (b) Asan Institute of Life Sciences, Laboratory of National Investment Project, Dept. of Rheumatology, Ulsan University Medical School, Seoul, Republic of Korea (c) Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA (d) Department of Maxillofacial Orthognathics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan Article History: Received 7 December 2009; Revised 17 May 2010; Accepted 19 May 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.06.018 Byline: A.V. Neutzsky-Wulff (a), N.A. Sims (b), C. Supanchart (c), U. Kornak (c)(d), D. Felsenberg (e), I.J. Poulton (b), T.J. Martin (b), M.A. Karsdal (a), K. Henriksen (a) Keywords: Endochondral ossification; CLCN7; ClC-7; Acidification; Osteopetrosis; Osteoclasts Abstract: Bone development is dependent on the functionality of three essential cell types: chondrocytes, osteoclasts and osteoblasts. If any of these cell types is dysfunctional, a developmental bone phenotype can result. The bone disease osteopetrosis is caused by osteoclast dysfunction or impaired osteoclastogenesis, leading to increased bone mass. In ClC-7 deficient mice, which display severe osteopetrosis, the osteoclast malfunction is due to abrogated acidification of the resorption lacuna. This study sought to investigate the consequences of osteoclast malfunction on bone development, bone structure and bone modeling/remodeling in ClC-7 deficient mice. Bones from wildtype, heterozygous and ClC-7 deficient mice were examined by bone histomorphometry and immunohistochemistry. ClC-7 deficient mice were found to have a severe developmental bone phenotype, characterized by dramatically increased bone mass, a high content of cartilage remnants, impaired longitudinal and radial growth, as well as lack of compact cortical bone development. Indices of bone formation were reduced in ClC-7 deficient mice; however, calcein labeling indicated that mineralization occurred on most trabecular bone surfaces. Osteoid deposition had great regional variance, but an osteopetrorickets phenotype, as observed in oc/oc mice, was not apparent in the ClC-7 deficient mice. A striking finding was the presence of very large abnormal osteoclasts, which filled the bone marrow space within the ClC-7 deficient bones. The development of these giant osteoclasts could be due to altered cell fate of the ClC-7 deficient osteoclasts, caused by increased cellular fusion and/or prolonged osteoclast survival. In summary, malfunctional ClC-7 deficient osteoclasts led to a severe developmental bone phenotype including abnormally large and non-functional osteoclasts. Bone formation paremeters were reduced; however, bone formation and mineralization were found to be heterogenous and continuing. Author Affiliation: (a) Nordic Bioscience A/S, Herlev, DK-2730, Denmark (b) St. Vincent's Institute, Melbourne, Victoria, Australia (c) Institute for Medical Genetics, Charite Universitaetsmedizin, Berlin, Germany (d) Max-Planck-Institut fur Molekulare Genetik, Berlin, Germany (e) Center for Muscle and Bone Research, Charite Campus Benjamin Franklin, Free University and Humboldt-University Berlin, Berlin, Germany Article History: Received 19 March 2010; Revised 11 June 2010; Accepted 14 June 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.01.008 Byline: Tripti Gaur (a), Sadiq Hussain (a), Rajini Mudhasani (a), Isha Parulkar (a), Jennifer L. Colby (a), Dana Frederick (a), Barbara E. Kream (b), Andre J. van Wijnen (a), Janet L. Stein (a), Gary S. Stein (a), Stephen N. Jones (a), Jane B. Lian (a) Keywords: Dicer ablation; MicroRNAs; Bone formation; Col1a-Cre; Osteocalcin-Cre; High bone mass; Osteoblast differentiation; Bone development Abstract: MicroRNA attenuation of protein translation has emerged as an important regulator of mesenchymal cell differentiation into the osteoblast lineage. A compelling question is the extent to which miR biogenesis is obligatory for bone formation. Here we show conditional deletion of the Dicer enzyme in osteoprogenitors by Col1a1-Cre compromised fetal survival after E14.5. A mechanism was associated with the post-commitment stage of osteoblastogenesis, demonstrated by impaired ECM mineralization and reduced expression of mature osteoblast markers during differentiation of mesenchymal cells of ex vivo deleted Dicer.sup.c/c. In contrast, in vivo excision of Dicer by Osteocalcin-Cre in mature osteoblasts generated a viable mouse with a perinatal phenotype of delayed bone mineralization which was resolved by 1month. However, a second phenotype of significantly increased bone mass developed by 2months, which continued up to 8months in long bones and vertebrae, but not calvariae. Cortical bone width and trabecular thickness in Dicer.sup.[DELTA]oc/[DELTA]oc was twice that of Dicer.sup.c/c controls. Normal cell and tissue organization was observed. Expression of osteoblast and osteoclast markers demonstrated increased coupled activity of both cell types. We propose that Dicer generated miRs are essential for two periods of bone formation, to promote osteoblast differentiation before birth, and control bone accrual in the adult. Author Affiliation: (a) Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA (b) Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030-1850, USA Article History: Received 24 June 2009; Revised 23 December 2009; Accepted 5 January 2010

A genome-wide association study and follow-up replication studies to identify genetic variants that influence bone mineral density (BMD) in different ethnic groups reveal that rs2273061 of the Jagged1 (JAG1) gene is associated with high BMD and osteoporotic fractures. The results reveal that the JAG1 gene is involved in BMD regulation in different ethnic groups, and is also a possible important factor in fracture pathogenesis.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.06.051 Byline: Vijay K. Yadav (1), Franck Oury (1), Nina Suda (1), Zhong-Wu Liu (2), Xiao-Bing Gao (2), Cyrille Confavreux (1), Kristen C. Klemenhagen (3), Kenji F. Tanaka (3)(4), Jay A. Gingrich (5), X. Edward Guo (6), Laurence H. Tecott (7), J. John Mann (8), Rene Hen (3), Tamas L. Horvath (2), Gerard Karsenty (1) Keywords: SYSNEURO Abstract: Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online. Author Affiliation: (1) Department of Genetics and Development, Columbia University, New York, NY 10032, USA (2) Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA (3) Department of Pharmacology, Columbia University, New York, NY 10032, USA (4) National Institute for Physiological Sciences, Okazaki 444-8585, Japan (5) Department of Psychiatry-Developmental Psychobiology, Columbia University, New York, NY 10032, USA (6) Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA (7) Department of Psychiatry, University of California, San Francisco, CA 94158, USA (8) Department of Psychiatry, Columbia University, New York, NY 10032, USA Article History: Received 23 January 2009; Revised 26 May 2009; Accepted 5 June 2009 Article Note: (miscellaneous) Published: September 3, 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajhg.2009.01.025 Byline: Dong-Hai Xiong (1), Xiao-Gang Liu (2), Yan-Fang Guo (2), Li-Jun Tan (3), Liang Wang (2), Bao-Yong Sha (3), Zi-Hui Tang (3), Feng Pan (2), Tie-Lin Yang (2), Xiang-Ding Chen (3), Shu-Feng Lei (3), Laura M. Yerges (5), Xue-Zen Zhu (2), Victor W. Wheeler (7), Alan L. Patrick (7), ClareAnn H. Bunker (5), Yan Guo (2), Han Yan (2), Yu-Fang Pei (2), Yin-Pin Zhang (1), Shawn Levy (8), Christopher J. Papasian (1), Peng Xiao (4), Y. Wang Lundberg (9), Robert R. Recker (4), Yao-Zhong Liu (1), Yong-Jun Liu (1), Joseph M. Zmuda (5)(6), Hong-Wen Deng (1)(2)(3)(4) Abstract: To identify and validate genes associated with bone mineral density (BMD), which is a prominent osteoporosis risk factor, we tested 379,319 SNPs in 1000 unrelated white U.S. subjects for associations with BMD. For replication, we genotyped the most significant SNPs in 593 white U.S. families (1972 subjects), a Chinese hip fracture (HF) sample (350 cases, 350 controls), a Chinese BMD sample (2955 subjects), and a Tobago cohort of African ancestry (908 males). Publicly available Framingham genome-wide association study (GWAS) data (2953 whites) were also used for in silico replication. The GWAS detected two BMD candidate genes, ADAMTS18 (ADAM metallopeptidase with thrombospondin type 1 motif, 18) and TGFBR3 (transforming growth factor, beta receptor III). Replication studies verified the significant findings by GWAS. We also detected significant associations with hip fracture for ADAMTS18 SNPs in the Chinese HF sample. Meta-analyses supported the significant associations of ADAMTS18 and TGFBR3 with BMD (p values: 2.56 x 10.sup.-5 to 2.13 x 10.sup.-8; total sample size: n = 5925 to 9828). Electrophoretic mobility shift assay suggested that the minor allele of one significant ADAMTS18 SNP might promote binding of the TEL2 factor, which may repress ADAMTS18 expression. The data from NCBI GEO expression profiles also showed that ADAMTS18 and TGFBR3 genes were differentially expressed in subjects with normal skeletal fracture versus subjects with nonunion skeletal fracture. Overall, the evidence supports that ADAMTS18 and TGFBR3 might underlie BMD determination in the major human ethnic groups. Author Affiliation: (1) Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA (2) The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China (3) Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China (4) Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA (5) Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA (6) Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA (7) Tobago Health Studies Office, Scarborough, Tobago, Trinidad and Tobago (8) Vanderbilt Microarray Shared Resource, Vanderbilt University, Nashville, TN 37232, USA (9) Genetics Department, Boys Town National Research Hospital, Omaha, NE, 68131, USA Article History: Received 3 November 2008; Revised 17 January 2009; Accepted 30 January 2009 Article Note: (miscellaneous) Published online: February 26, 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.10.014 Byline: S.J. Choi (a), G.D. Roodman (b), J.Q. Feng (c), I.S. Song (a), K. Amin (a), P.S. Hart (d), J.T. Wright (e), N. Haruyama (f), T.C. Hart (a) Keywords: Rodent; Transgenic mice; DLX3; Osteoclast; Bone mineralization; Interferon-gamma Abstract: Distal-less 3 (DLX3) gene mutations are etiologic for Tricho-Dento-Osseous syndrome. To investigate the in vivo impact of mutant DLX3 on bone development, we established transgenic (TG) mice expressing the c.571_574delGGGG DLX-3 gene mutation (MT-DLX3) driven by a mouse 2.3 Col1A1 promoter. Microcomputed tomographic analyses demonstrated markedly increased trabecular bone volume and bone mineral density in femora from TG mice. In ex vivo experiments, TG mice showed enhanced differentiation of bone marrow stromal cells to osteoblasts and increased expression levels of bone formation markers. However, TG mice did not show enhanced dynamic bone formation rates in in vivo fluorochrome double labeling experiments. Osteoclastic differentiation capacities of bone marrow monocytes were reduced in TG mice in the presence of osteoclastogenic factors and the numbers of TRAP(+) osteoclasts on distal metaphyseal trabecular bone surfaces were significantly decreased. TRACP 5b and CTX serum levels were significantly decreased in TG mice, while IFN-[gamma] levels were significantly increased. These data demonstrate that increased levels of IFN-[gamma] decrease osteoclast bone resorption activities, contributing to the enhanced trabecular bone volume and mineral density in these TG mice. These data suggest a novel role for this DLX-3 mutation in osteoclast differentiation and bone resorption. Author Affiliation: (a) Human Craniofacial Genetics Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20854, USA (b) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA (c) Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA (d) Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA (e) Department of Pediatric Dentistry, University of North, Chapel Hill, NC, USA (f) Division of Oral Dysfunction Science, Tohoku University, Graduate School of Dentistry, Sendai, Japan Article History: Received 1 August 2008; Revised 5 September 2008; Accepted 2 October 2008

A case-control genome-wide copy-number variation (CNV) study is conducted, which proves UGT2B17 to be a gene likely to be associated with osteoporosis, a highly heritable disease. A higher UGT2B17 gene copy number is shown to lead to lower bone-mineral density (BMD), poor bone quality and increased susceptibility to osteoporosis fractures (OF) in the patients.

The aim of this study was to determine whether body mass index (BMI) influences the risk of low back pain (LBP) in a population exposed to whole body vibration (WBV). For this a self-administered questionnaire was sent to 467 participants, driving occupational vehicles. Vibration measurements were performed according to ISO 2631-1 on a representative sample (n = 30) of this population. For each participant, we calculated the current root mean square (r.m.s.) over an 8 h (A(8)) working day. The questionnaire response rate was 47% (n = 221). We did not find a significant correlation between BMI and the onset of LBP in the last 7 days (r = 0.07, p = 0.34) nor for LBP in past 12 months (r = -0.30, p = 0.63). No significant increased risk was found for the onset of LBP with the increase of BMI, neither for the last 7 days (OR 1.02; 95% CI: 0.93-1.23) nor for the past 12 months LBP (OR 0.98: 95% CI: 0.89-1.09). Introducing the interaction with WBV exposure in the logistic regression model, did not result a significant increased risk in the onset of LB--7 days (OR 0.97; 95% CI: 0.92-1.01) nor in the onset of LBP 12 months (OR 0.97; 95% CI: 0.93-1.01) either. Occupational participants exposed to WBV, with a high BMI do not have an increased risk for the development of LBP. Keywords: Low back pain; Whole body vibration; Body mass index

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.01.051 Byline: Li Sun (1), Yuanzhen Peng (1), Allison C. Sharrow (2)(3), Jameel Iqbal (1), Zhiyuan Zhang (1), Dionysios J. Papachristou (2)(3), Samir Zaidi (1), Ling-Ling Zhu (1), Beatrice B. Yaroslavskiy (2)(3), Hang Zhou (1), Alberta Zallone (4), M. Ram Sairam (5), T. Rajendra Kumar (6), Wei Bo (7), Jonathan Braun (7), Luis Cardoso-Landa (1), Mitchell B. Schaffler (1), Baljit S. Moonga (1), Harry C. Blair (2)(3), Mone Zaidi (1) Abstract: Postmenopausal osteoporosis, a global public health problem, has for decades been attributed solely to declining estrogen levels. Although FSH levels rise sharply in parallel, a direct effect of FSH on the skeleton has never been explored. We show that FSH is required for hypogonadal bone loss. Neither FSH[beta] nor FSH receptor (FSHR) null mice have bone loss despite severe hypogonadism. Bone mass is increased and osteoclastic resorption is decreased in haploinsufficient FSH[beta].sup.+/- mice with normal ovarian function, suggesting that the skeletal action of FSH is estrogen independent. Osteoclasts and their precursors possess G.sub.i2[alpha]-coupled FSHRs that activate MEK/Erk, NF-[kappa]B, and Akt to result in enhanced osteoclast formation and function. We suggest that high circulating FSH causes hypogonadal bone loss. Author Affiliation: (1) Mount Sinai Bone Program, Department of Medicine and Department of Orthopedics, Mount Sinai School of Medicine, New York, NY 10029, USA (2) Departments of Pathology and Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA (3) VA Medical Center, Pittsburgh, PA 15261, USA (4) Department of Anatomy and Histology, University of Bari, 70124 Bari, Italy (5) Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, Canada (6) Department of Molecular and Integrative Physiology, University of Kansas, Kansas City, KS 66160, USA (7) Department of Pathology, University of California, Los Angeles, Los Angeles, CA 90095, USA Article History: Received 9 March 2005; Revised 2 September 2005; Accepted 23 January 2006 Article Note: (miscellaneous) Published: April 20, 2006

Postmenopausal osteoporosis, a global public health problem, is attributed solely to estrogen levels, and although FSH levels rise sharply in parallel, a direct effect of FSH on the skeleton is never explored. After menopause, resorption significantly exceeds formation, and this imbalance results in net bone loss, while estrogen replacement slows postmenopausal bone loss, thus reducing the risk of fracture.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.06.028 Byline: Loning Fu (1)(2), Millan S. Patel (1)(2), Allan Bradley (4), Erwin F. Wagner (5), Gerard Karsenty (1)(2)(3) Abstract: The hormone leptin is a regulator of bone remodeling, a homeostatic function maintaining bone mass constant. Mice lacking molecular-clock components (Per and Cry), or lacking Per genes in osteoblasts, display high bone mass, suggesting that bone remodeling may also be subject to circadian regulation. Moreover, Per-deficient mice experience a paradoxical increase in bone mass following leptin intracerebroventricular infusion. Thus, clock genes may mediate the leptin-dependent sympathetic regulation of bone formation. We show that expression of clock genes in osteoblasts is regulated by the sympathetic nervous system and leptin. Clock genes mediate the antiproliferative function of sympathetic signaling by inhibiting G1 cyclin expression. Partially antagonizing this inhibitory loop, leptin also upregulates AP-1 gene expression, which promotes cyclin D1 expression, osteoblast proliferation, and bone formation. Thus, leptin determines the extent of bone formation by modulating, via sympathetic signaling, osteoblast proliferation through two antagonistic pathways, one of which involves the molecular clock. Author Affiliation: (1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 (2) Bone Disease Program of Texas, Baylor College of Medicine, Houston, Texas 77030 (3) Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030 (4) Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom (5) Research Institute of Molecular Pathology, A-1030 Vienna, Austria Article History: Received 21 April 2005; Revised 2 June 2005; Accepted 14 June 2005 Article Note: (miscellaneous) Published: September 8, 2005

Archaeologists are interested in how human prey choice decisions vary both spatially and temporally where research is focused on the role of climate and human overhunting play in the process. The faunal record from two Fremont residential sites located in Utah's Parowan Valley shows patterns of taxonomic representation, age structure, element representation, and fragmentation which covary through time both with each other and with local tree-ring records.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.04.028 Byline: Zhousheng Xiao (a), Hani A. Awad (b), Shiguang Liu (a), Josh Mahlios (a), Shiqin Zhang (a), Farshid Guilak (c), Matthew S. Mayo (d), Leigh Darryl Quarles (a) Keywords: Runx2-II; Knockout; Osteopenia; Osteoblast; Osteoclast; Hypertrophic chondrocyte; Trabecular bone; Cortical bone; Remodeling; Mouse Abstract: Runx2 transcribes Runx2-II and Runx2-I isoforms with distinct N-termini. Deletion of both isoforms results in complete arrest of bone development, whereas selective loss of Runx2-II is sufficient to form a grossly intact skeleton with impaired endochondral bone development. To elucidate the role of Runx2-II in osteoblast function in adult mice, we examined heterozygous Runx2-II (Runx2-II.sup.+/-) and homozygous Runx2-II (Runx2-II.sup.-/-)-deficient mice, which, respectively, lack one or both copies of Runx2-II but intact Runx2-I expression. Compared to wild-type mice, 6-week-old Runx2-II.sup.+/- had reduced trabecular bone volume (BV/TV%), cortical thickness (Ct.Th), and bone mineral density (BMD), decreased osteoblastic and osteoclastic markers, lower bone formation rates, impaired osteoblast maturation of BMSCs in vitro, and significant reductions in mechanical properties. Homozygous Runx2-II.sup.-/- mice had a more severe reduction in BMD, BV/TV%, and Ct.Th, and greater suppression of osteoblastic and osteoclastic markers than Runx2-II.sup.+/- mice. Non-selective Runx2.sup.+/- mice, which have an equivalent reduction in Runx2 expression due to the lack one copy of Runx2-I and II, however, had an intermediate reduction in BMD. Thus, selective Runx2-II mutation causes diminished osteoblastic function in an adult mouse leading to low-turnover osteopenia and suggest that Runx2-I and II have distinct functions imparted by their different N-termini. Author Affiliation: (a) Internal Medicine/The Kidney Institute, University of Kansas Medical Center, MS 3018, 3901 Rainbow Boulevard, 6018 Wahl Hall East, Kansas City, KS 66160, USA (b) Biomedical Engineering/Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA (c) Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA (d) Center for Biostatitics and Advanced Informatics, University of Kansas Medical Center, Kansas City, KS 66160, USA Article History: Received 15 February 2005; Revised 21 April 2005; Accepted 22 April 2005

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.01.035 Byline: Motozo Yamashita (1), Sai-Xia Ying (1), Gen-mu Zhang (2), Cuiling Li (3), Steven Y. Cheng (1), Chu-xia Deng (3), Ying E. Zhang (1) Abstract: Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGF[beta] or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation. Author Affiliation: (1) Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 (2) Laboratory Animal Science Program, National Cancer Institute at Frederick, Frederick, Maryland 21702 (3) Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 Article History: Received 9 July 2004; Revised 24 November 2004; Accepted 20 January 2005 Article Note: (miscellaneous) Published: April 7, 2005

Results show that the bone remodeling mediated by osteoblasts and osteoclasts is controlled by osteoblast proliferation and differentiation through bone morphogenetic protein and Smad proteins. Data indicate Tob is an antiproliferation protein and negatively regulates the above process by suppressing the activity of the Smad proteins.