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Bone Biology

  • 142 Articles
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A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders
Robert C. Gensure, … , William G. Cole, Harald Jüppner
Robert C. Gensure, … , William G. Cole, Harald Jüppner
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1250-1257. https://doi.org/10.1172/JCI22760.
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A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders

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Abstract

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040C↠T) in exon 41 of the gene encoding the α1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric α1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.

Authors

Robert C. Gensure, Outi Mäkitie, Catherine Barclay, Catherine Chan, Steven R. DePalma, Murat Bastepe, Hilal Abuzahra, Richard Couper, Stefan Mundlos, David Sillence, Leena Ala Kokko, Jonathan G. Seidman, William G. Cole, Harald Jüppner

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An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression
Michael Niedermaier, … , Paul B. Selby, Stefan Mundlos
Michael Niedermaier, … , Paul B. Selby, Stefan Mundlos
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):900-909. https://doi.org/10.1172/JCI23675.
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An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression

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Abstract

Short digits (Dsh) is a radiation-induced mouse mutant. Homozygous mice are characterized by multiple defects strongly resembling those resulting from Sonic hedgehog (Shh) inactivation. Heterozygous mice show a limb reduction phenotype with fusion and shortening of the proximal and middle phalanges in all digits, similar to human brachydactyly type A1, a condition caused by mutations in Indian hedgehog (IHH). We mapped Dsh to chromosome 5 in a region containing Shh and were able to demonstrate an inversion comprising 11.7 Mb. The distal breakpoint is 13.298 kb upstream of Shh, separating the coding sequence from several putative regulatory elements identified by interspecies comparison. The inversion results in almost complete downregulation of Shh expression during E9.5–E12.5, explaining the homozygous phenotype. At E13.5 and E14.5, however, Shh is upregulated in the phalangeal anlagen of Dsh/+ mice, at a time point and in a region where WT Shh is never expressed. The dysregulation of Shh expression causes the local upregulation of hedgehog target genes such as Gli1-3, patched, and Pthlh, as well as the downregulation of Ihh and Gdf5. This results in shortening of the digits through an arrest of chondrocyte differentiation and the disruption of joint development.

Authors

Michael Niedermaier, Georg C. Schwabe, Stephan Fees, Anne Helmrich, Norbert Brieske, Petra Seemann, Jochen Hecht, Volkhard Seitz, Sigmar Stricker, Gundula Leschik, Evelin Schrock, Paul B. Selby, Stefan Mundlos

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Essential role of RSK2 in c-Fos–dependent osteosarcoma development
Jean-Pierre David, … , Michael Amling, Erwin F. Wagner
Jean-Pierre David, … , Michael Amling, Erwin F. Wagner
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):664-672. https://doi.org/10.1172/JCI22877.
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Essential role of RSK2 in c-Fos–dependent osteosarcoma development

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Abstract

Inactivation of the growth factor–regulated S6 kinase RSK2 causes Coffin-Lowry syndrome in humans, an X-linked mental retardation condition associated with progressive skeletal abnormalities. Here we show that mice lacking RSK2 develop a progressive skeletal disease, osteopenia due to impaired osteoblast function and normal osteoclast differentiation. The phenotype is associated with decreased expression of Phex, an endopeptidase regulating bone mineralization. This defect is probably not mediated by RSK2-dependent phosphorylation of c-Fos on serine 362 in the C-terminus. However, in the absence of RSK2, c-Fos–dependent osteosarcoma formation is impaired. The lack of c-Fos phosphorylation leads to reduced c-Fos protein levels, which are thought to be responsible for decreased proliferation and increased apoptosis of transformed osteoblasts. Therefore, RSK2-dependent stabilization of c-Fos is essential for osteosarcoma formation in mice and may also be important for human osteosarcomas.

Authors

Jean-Pierre David, Denis Mehic, Latifa Bakiri, Arndt F. Schilling, Vice Mandic, Matthias Priemel, Maria Helena Idarraga, Markus O. Reschke, Oskar Hoffmann, Michael Amling, Erwin F. Wagner

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IL-1 mediates TNF-induced osteoclastogenesis
Shi Wei, … , F. Patrick Ross, Steven L. Teitelbaum
Shi Wei, … , F. Patrick Ross, Steven L. Teitelbaum
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):282-290. https://doi.org/10.1172/JCI23394.
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IL-1 mediates TNF-induced osteoclastogenesis

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Abstract

TNF-induced receptor activator NF-κB ligand (RANKL) synthesis by bone marrow stromal cells is a fundamental component of inflammatory osteolysis. We found that this process was abolished by IL-1 receptor antagonist (IL-1Ra) or in stromal cells derived from type I IL-1 receptor–deficient (IL-1RI–deficient) mice. Reflecting sequential signaling of the cytokines TNF and IL-1, TNF induces stromal cell expression of IL-1 and IL-1RI. These data suggest that TNF regulates RANKL expression via IL-1, and, therefore, IL-1 plays a role in TNF-induced periarticular osteolysis. Consistent with this posture, TNF-stimulated osteoclastogenesis in cultures consisting of WT marrow macrophages and stromal cells exposed to IL-1Ra or in cocultures established with IL-1RI–deficient stromal cells was reduced approximately 50%. The same magnitude of osteoclast inhibition occurred in IL-1RI–deficient mice following TNF administration in vivo. Like TNF, IL-1 directly targeted osteoclast precursors and promoted the osteoclast phenotype in a TNF-independent manner in the presence of permissive levels of RANKL. IL-1 is able to induce RANKL expression by stromal cells and directly stimulate osteoclast precursor differentiation under the aegis of p38 MAPK. Thus, IL-1 mediates the osteoclastogenic effect of TNF by enhancing stromal cell expression of RANKL and directly stimulating differentiation of osteoclast precursors.

Authors

Shi Wei, Hideki Kitaura, Ping Zhou, F. Patrick Ross, Steven L. Teitelbaum

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A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells
Masako Miura, … , Marian Young, Songtao Shi
Masako Miura, … , Marian Young, Songtao Shi
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1704-1713. https://doi.org/10.1172/JCI20427.
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A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells

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Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification and decreased bone mineral density in caspase-3–deficient (Casp3–/– and Casp3+/–) mice due to an attenuated osteogenic differentiation of bone marrow stromal stem cells (BMSSCs). The mechanism involved in the impaired differentiation of BMSSCs is due, at least partially, to the overactivated TGF-β/Smad2 signaling pathway and the upregulated expressions of p53 and p21 along with the downregulated expressions of Cdk2 and Cdc2, and ultimately increased replicative senescence. In addition, the overactivated TGF-β/Smad2 signaling may result in the compromised Runx2/Cbfa1 expression in preosteoblasts. Furthermore, we demonstrate that caspase-3 inhibitor, a potential agent for clinical treatment of human diseases, caused accelerated bone loss in ovariectomized mice, which is also associated with the overactivated TGF-β/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-β/Smad2 pathway and cell cycle progression.

Authors

Masako Miura, Xiao-Dong Chen, Matthew R. Allen, Yanming Bi, Stan Gronthos, Byoung-Moo Seo, Saquib Lakhani, Richard A. Flavell, Xin-Hua Feng, Pamela Gehron Robey, Marian Young, Songtao Shi

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Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation
Fumiyo Ikeda, … , Anjana Rao, Toshiyuki Yoneda
Fumiyo Ikeda, … , Anjana Rao, Toshiyuki Yoneda
Published August 16, 2004
Citation Information: J Clin Invest. 2004;114(4):475-484. https://doi.org/10.1172/JCI19657.
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Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation

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Abstract

Receptor activator of NF-κB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-κB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase–positive (TRAP–positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.

Authors

Fumiyo Ikeda, Riko Nishimura, Takuma Matsubara, Sakae Tanaka, Jun-ichiro Inoue, Sakamuri V. Reddy, Kenji Hata, Kenji Yamashita, Toru Hiraga, Toshiyuki Watanabe, Toshio Kukita, Katsuji Yoshioka, Anjana Rao, Toshiyuki Yoneda

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Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy
Hisako Hikiji, … , Tsuyoshi Takato, Takao Shimizu
Hisako Hikiji, … , Tsuyoshi Takato, Takao Shimizu
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):85-93. https://doi.org/10.1172/JCI20504.
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Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy

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Abstract

While platelet-activating factor (PAF) is produced in various diseases associated with bone resorption, its functions in bone metabolism remain unknown. Using PAF receptor–deficient mice, we evaluated the role of PAF in the development of bone resorption following ovariectomy, a model of postmenopausal osteoporosis. Through observations of bone mineral density and histomorphometric parameters, it was found that bone resorption was markedly attenuated in PAF receptor–deficient mice, indicating that PAF links estrogen depletion and osteoporosis in vivo. Osteoclasts expressed higher amounts of the enzymes required for PAF biosynthesis than osteoblasts. TNF-α and IL-1β increased the acetyl-coenzyme A:lyso-PAF acetyltransferase activity in osteoclasts. Osteoclasts, but not osteoblasts, expressed the functional PAF receptor. PAF receptor stimulation prolonged the survival of osteoclasts in vitro. Furthermore, osteoclasts treated with a PAF receptor antagonist, and also those from PAF receptor–deficient mice, showed reductions in survival rate and Ca resorption activity. Consistently, in organ cultures, bone resorption was significantly suppressed by a PAF receptor antagonist treatment or genetic PAF receptor deficiency. Thus, these results suggest that, through the inflammatory cytokines, estrogen depletion enhances PAF production as a unique autocrine factor for osteoclast functions. Inhibition of PAF function might pave the way for a new strategy to prevent postmenopausal bone loss without disturbing osteoblast functions.

Authors

Hisako Hikiji, Satoshi Ishii, Hideo Shindou, Tsuyoshi Takato, Takao Shimizu

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The cyclin-dependent kinase inhibitor p57Kip2 mediates proliferative actions of PTHrP in chondrocytes
Helen E. MacLean, … , David Cobrinik, Henry M. Kronenberg
Helen E. MacLean, … , David Cobrinik, Henry M. Kronenberg
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1334-1343. https://doi.org/10.1172/JCI21252.
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The cyclin-dependent kinase inhibitor p57Kip2 mediates proliferative actions of PTHrP in chondrocytes

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Abstract

Parathyroid hormone–related peptide (PTHrP) is a positive regulator of chondrocyte proliferation during bone development. In embryonic mice lacking PTHrP, chondrocytes stop proliferating prematurely, with accelerated differentiation. Because the bone phenotype of mice lacking the cyclin-dependent kinase inhibitor p57Kip2 is the opposite of the PTHrP-null phenotype, we hypothesized that PTHrP’s proliferative actions in chondrocytes might be mediated by opposing p57. We generated p57/PTHrP-null embryos, which showed partial rescue of the PTHrP-null phenotype. There was reversal of the loss of proliferative chondrocytes in most bones, with reversal of the accelerated differentiation that occurs in the PTHrP-null phenotype. p57 mRNA and protein were upregulated in proliferative chondrocytes in the absence of PTHrP. Metatarsal culture studies confirmed the action of PTHrP to decrease p57 mRNA and protein levels in a model in which parathyroid hormone (PTH), used as an analog of PTHrP, increased chondrocyte proliferation rate and the length of the proliferative domain. PTH treatment of p57-null metatarsals had no effect on proliferation rate in round proliferative chondrocytes but still stimulated proliferation in columnar chondrocytes. These studies suggest that the effects of PTHrP on both the rate and extent of chondrocyte proliferation are mediated, at least in part, through suppression of p57 expression.

Authors

Helen E. MacLean, Jun Guo, Melissa C. Knight, Pumin Zhang, David Cobrinik, Henry M. Kronenberg

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PPAR γ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors
Toru Akune, … , Takashi Kadowaki, Hiroshi Kawaguchi
Toru Akune, … , Takashi Kadowaki, Hiroshi Kawaguchi
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):846-855. https://doi.org/10.1172/JCI19900.
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PPAR γ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors

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Abstract

Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARγ-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARγ gene. Heterozygous PPARγ-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARγ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ-dependent regulation of bone metabolism in vivo, in that PPARγ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.

Authors

Toru Akune, Shinsuke Ohba, Satoru Kamekura, Masayuki Yamaguchi, Ung-il Chung, Naoto Kubota, Yasuo Terauchi, Yoshifumi Harada, Yoshiaki Azuma, Kozo Nakamura, Takashi Kadowaki, Hiroshi Kawaguchi

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Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts
Hiroaki Seto, … , Hiroshi Kawaguchi, Sakae Tanaka
Hiroaki Seto, … , Hiroshi Kawaguchi, Sakae Tanaka
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):718-726. https://doi.org/10.1172/JCI19899.
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Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts

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Abstract

The role of TGF-β/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector–mediated gene transduction system. Expression of constitutively active activin receptor–like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.

Authors

Hiroaki Seto, Satoshi Kamekura, Toshiki Miura, Aiichiro Yamamoto, Hirotaka Chikuda, Toru Ogata, Hisatada Hiraoka, Hiromi Oda, Kozo Nakamura, Hisashi Kurosawa, Ung-il Chug, Hiroshi Kawaguchi, Sakae Tanaka

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