Forced chondrocyte expression of sonic hedgehog impairs joint formation affecting proliferation and apoptosis

Tavella, Sara; Biticchi, Roberta; Morello, Roy; Castagnola, Patrizio; Musante, Veronica; Costa, Delfina; Cancedda, Ranieri; Garofalo, Silvio

doi:10.1016/j.matbio.2006.07.005

Cited by 11 publications

(6 citation statements)

References 46 publications

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“…Differences between expression level/number of infected cells and timing of ectopic SHH expression may account for the difference. Ectopic expression of SHH from a chondrocyte-specific promoter in transgenic mice leads to carpal and tarsal joint separation defects (Tavella et al, 2006), and as chondrocyte progenitors are readily infected by the QC viruses, a similar defect may have occurred here.…”

Section: Research Articlementioning

confidence: 81%

Pseudotyped retroviruses for infecting axolotl in vivo and in vitro

et al. 2013

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SUMMARYAxolotls are poised to become the premiere model system for studying vertebrate appendage regeneration. However, very few molecular tools exist for studying crucial cell lineage relationships over regeneration or for robust and sustained misexpression of genetic elements to test their function. Furthermore, targeting specific cell types will be necessary to understand how regeneration of the diverse tissues within the limb is accomplished. We report that pseudotyped, replication-incompetent retroviruses can be used in axolotls to permanently express markers or genetic elements for functional study. These viruses, when modified by changing their coat protein, can infect axolotl cells only when they have been experimentally manipulated to express the receptor for that coat protein, thus allowing for the possibility of targeting specific cell types. Using viral vectors, we have found that progenitor populations for many different cell types within the blastema are present at all stages of limb regeneration, although their relative proportions change with time.

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Section: Research Articlementioning

confidence: 81%

Pseudotyped retroviruses for infecting axolotl in vivo and in vitro

et al. 2013

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“…Retroviralinduced misexpression of Shh at high concentrations within the digital rays of chicken limbs blocks the formation of joints (27). In addition, Shh misexpression in the chondrocytes of developing mouse digits under the control of a procollagen gene promoter blocks joint formation and promotes cell proliferation (28). Thus, the high Shh concentration surrounding the forelimb digits in the bat may have the same effect, allowing the cells of the digital rays to proliferate and suppressing the joint-formation pathway until after Shh expression ceases.…”

Section: Discussionmentioning

confidence: 99%

A second wave of Sonic hedgehog expression during the development of the bat limb

Hockman¹,

Cretekos

Mason

et al. 2008

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

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Sonic hedgehog (Shh) plays an integral role in both the anteriorposterior (A-P) patterning and expansion of developing vertebrate limbs through a feedback loop involving Fgfs, Bmps, and Gremlin. In bat limbs A-P patterning and the size of the digital field are unique. The posterior digits of the forelimb are elongated and joined by tissue, whereas the thumb is short. The hindlimb digits often are uniform in length. Here, we reveal novel expression patterns for Shh and its target, Patched 1 (Ptc1), during limb development in two bat species. Early Shh expression in the zone of polarizing activity is wider in the bat forelimb than in the mouse forelimb, correlating with the reported expansion of Fgf8 expression in the apical ectodermal ridge and the early loss of symmetry in the bat forelimb. Later in limb development, Shh and Ptc1 expression is reinitiated in the interdigital tissue. Shh is graded along the A-P axis in forelimb and is expressed uniformly at a lower level across the hindlimb interdigital tissue. We also show that the reported Fgf8 expression in the interdigital tissue precedes the expression of Shh. We propose that the reinitiation of Shh and Fgf8 expression in bat limbs reactivates the Shh-Fgf feedback loop in the interdigital tissue of stage 16 bat embryos. The cell survival and proliferation signals provided by the Shh-Fgf signaling loop probably contribute to the lengthening of the posterior forelimb digits, the survival of the forelimb interdigital webbing, and the extension of the hindlimb digits to a uniform length.Miniopterus natalensis ͉ Carollia perspicillata ͉ Patched1 ͉ Fgf8 ͉ evo-devo

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“…It has previously been documented that IHH signaling is important for normal chondrocyte growth and differentiation and is involved in joint formation (). In the growth plate of the limbs, forced expression of either sonic HH or IHH activates chondrocyte proliferation and impairs joint formation (). In the lumbar spine, chondrocyte proliferation and HH responsiveness measured by a Gli‐1 reporter ceases during aging.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation

Dittmann

Wuelling

Uhmann

et al. 2014

Arthritis & Rheumatology

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Objective. During development of the vertebrate skeleton, chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (HH) family have been implicated in the ossification process, but their exact relationship to normal or pathogenic bone formation is unclear. This study was undertaken to establish a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and to investigate in vivo how chondrocyte-specific ablation of the inhibitory HH receptor Patched 1 (Ptch1) affects skeleton integrity.Methods. A Cre-deleter mouse strain, mb1-Cre, for selective gene recombination in spinal chondrocytes was identified by in situ hybridization and histologic analysis. The mb1-Cre ؉/؊ animals were crossed with mice that harbor a loxP-flanked Ptch1 gene (Ptch1 flox/flox ) to abrogate the inhibition of the HH signaling pathway in chondrocytes. The skeletal integrity of F1 mice was characterized by high-resolution flat-panel-based volume computed tomography and histologic staining procedures.Results. During the first weeks after birth, all mb1-Cre ؉/؊ /Ptch1 flox/flox mice developed progressive spinal fusion with malformation of the vertebrae. This phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner. Conclusion.Our findings indicate that chronic activation of the HH signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin.Development of the axial and appendicular skeleton of vertebrates is initiated by local condensation of mesenchymal cells and their differentiation into chondrocytes, which form cartilage anlagen (1,2). Proper ossification of the anlagen is associated with a complex chondrocyte maturation program (3). Small, highly proliferating chondrocytes produce extracellular matrix proteins that comprise types II, IX, and XI collagen as well as the proteoglycan aggrecan.Indian hedgehog (IHH), a member of the hedgehog (HH) family of secreted morphogens, and parathyroid hormone-related protein (PTHrP) have been reported to maintain chondrocytes in a proliferative state (4-7). Other growth factors, such as thyroid hormone or bone morphogenic proteins, antagonize the actions of IHH and PTHrP, thereby promoting cell cycle exit. This is followed by terminal differentiation of chondrocytes into hypertrophic cells, which secrete type X collagen (ColX) and ultimately die by apoptosis. Following its calcification, the cartilage matrix provides a template for the balanced action of hematopoietic osteoclasts and mesenchyme-derived osteoblasts to finalize bone formation. The long bones and the vertebrae of the spinal column are connected by synovial joints and intervertebral discs, respectively.Chondrogenesis and endochondral oss...

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Forced chondrocyte expression of sonic hedgehog impairs joint formation affecting proliferation and apoptosis

Cited by 11 publications

References 46 publications

Pseudotyped retroviruses for infecting axolotl in vivo and in vitro

Pseudotyped retroviruses for infecting axolotl in vivo and in vitro

A second wave of Sonic hedgehog expression during the development of the bat limb

Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation

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