Impaired endochondral bone development and osteopenia in Gli2-deficient mice

Miao, Dengshun; Liu, Hanlong; Plut, Paul; Niu, Meijuan; Huo, Rujuan; Goltzman, David; Henderson, Janet E.

doi:10.1016/j.yexcr.2003.10.021

Cited by 78 publications

(62 citation statements)

References 49 publications

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“…We 72 and Hh signaling is important in regulating cell cycle regulators in stem cells to control hematopoietic regeneration 160 . Therefore, Hh signaling blockade in humans must circumvent these potential side-effects in order to emerge as a bonafide therapy.…”

Section: Hh Signaling Regulates Adamts5 Expression Through Runx2mentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

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Section: Hh Signaling Regulates Adamts5 Expression Through Runx2mentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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“…Gli2 was one of the most highly enriched genes in our screen. To define its functional role in TMJ formation, we examined mice homozygous for targeted disruption of the Gli2 zinc finger domain (Gli2 zfd/zfd ), which abrogates the DNA binding function of the protein (30). Gli2 mutants were compared with wild-type littermates (Fig.…”

Section: Comparison Of Gene Expression In the Tmj And Other Synovial mentioning

confidence: 99%

“…Thus, our experiments strongly suggest that the formation of the TMJ disk requires Gli2 activity. Interestingly, Gli2 mutant mice also fail to develop intervertebral disks (29,30), which are similar to the TMJ disk in that they consist of fibrocartilage. In a few instances, the TMJ disk was absent from one side of the mandible but was present or incompletely formed on the contralateral side, indicating that the Gli2 mutation is not fully penetrant with respect to the TMJ phenotype.…”

Section: Comparison Of Gene Expression In the Tmj And Other Synovial mentioning

confidence: 99%

“…Finally, Gli2 functions mostly as a transcriptional activator, although in the absence of Ihh activity it retains some repressor function (27,28). Functional Gli2 is necessary for normal endochondral bone development, as indicated in mice lacking the Gli2 gene (29,30), whereas in early limb development Gli3 is the only significant mediator of hedgehog (Hh) signaling (downstream of the Ihh-relative, Sonic hedgehog) (31). During skeletogenesis, the three Gli family members are active and exhibit some degree of functional redundancy in mediating Ihh signaling (27,29).…”

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confidence: 99%

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Temporomandibular joint formation requires two distinct hedgehog-dependent steps

Purcell

Joo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

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We conducted a genetic analysis of the developing temporo-mandibular or temporomandi-bular joint (TMJ), a highly specialized synovial joint that permits movement and function of the mammalian jaw. First, we used laser capture microdissection to perform a genome-wide expression analysis of each of its developing components. The expression patterns of genes identified in this screen were examined in the TMJ and compared with those of other synovial joints, including the shoulder and the hip joints. Striking differences were noted, indicating that the TMJ forms via a distinct molecular program. Several components of the hedgehog ( Hh ) signaling pathway are among the genes identified in the screen, including Gli2 , which is expressed specifically in the condyle and in the disk of the developing TMJ. We found that mice deficient in Gli2 display aberrant TMJ development such that the condyle loses its growth-plate-like cellular organization and no disk is formed. In addition, we used a conditional strategy to remove Smo , a positive effector of the Hh signaling pathway, from chondrocyte progenitors. This cell autonomous loss of Hh signaling allows for disk formation, but the resulting structure fails to separate from the condyle. Thus, these experiments establish that Hh signaling acts at two distinct steps in disk morphogenesis, condyle initiation, and disk–condyle separation and provide a molecular framework for future studies of the TMJ.

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“…Hh inhibits Gli processing and converts the full-length Gli proteins into transcriptional activators. Both Gli2 and Gli3 play important roles in the regulation of bone formation downstream of Ihh (9)(10)(11)(12).…”

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confidence: 99%

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Cai

Liu

2016

Proc. Natl. Acad. Sci. U.S.A.

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Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckletype POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling. Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Finally, we demonstrate in a conditional mutant that loss of Spop results in brachydactyly and osteopenia, which can be rescued by reducing the dosage of Gli3. In summary, Spop is an important positive regulator of Ihh signaling and skeletal development.T he human skeleton provides essential mechanical support, mobility, and mineral storage critical for health (1). In development, most bones form through endochondral ossification in which chondrocytes in the growth plate proliferate, undergo hypertrophic differentiation, and secrete calcium-containing extracellular matrix (2). The osteoblasts in the perichondrium, a thin layer of tissue surrounding the cartilage, replace the dying chondrocytes and secrete more bone matrix. On the other hand, osteoclasts, derived from white blood cells, invade and digest bone matrix. The balance between the osteoblast and osteoclast activities allows calcium homeostatic control and bone health. In osteopenia and osteoporosis, conditions afflicting more than 10 million Americans, an abnormal decrease in osteoblast activity or increase in osteoclast activity results in the loss of bone mass (1, 3). Unfortunately, our understanding of these bone diseases has been hindered by incomplete knowledge in the molecular mechanisms underlying endochondral bone development and remodeling.Indian Hedgehog (Ihh), a member of the Hedgehog (Hh) family of signaling proteins, is essential for endochondral bone development (4). Ihh regulates gene expression through the Gli family of transcription factors, which act as both transcriptional activators and repressors (5). In the absence of Hh, efficient proteolytic processing turns Gli3 into a transcriptional repressor (Gli3R) whereas processing of Gli2 is rather inefficient (6-8). Hh inhibits Gli processing and converts the full-length Gli proteins into transcriptional activators. Both Gli2 and Gli3 play important roles in the regulation of bone formation downstream of Ihh (9-12).Ihh maintains the expression of parathyroid hormone-like peptide (Pthlh) (Mouse Genome Informatics) in the periarticular perichondrium (13), which then stimulates the prol...

show abstract

Impaired endochondral bone development and osteopenia in Gli2-deficient mice

Cited by 78 publications

References 49 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Temporomandibular joint formation requires two distinct hedgehog-dependent steps

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

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