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| 2. |
- Batkovskyte, D., et al.
(författare)
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Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders
- 2023
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 38:5, s. 692-706
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Tidskriftsartikel (refereegranskat)abstract
- Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located.
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| 3. |
- Chen, Yin Huai, et al.
(författare)
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Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
- 2020
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:3
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Tidskriftsartikel (refereegranskat)abstract
- The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.
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| 4. |
- Kaucka, Marketa, et al.
(författare)
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Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage
- 2017
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Ingår i: eLIFE. - : Elife Sciences Publications LTD. - 2050-084X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale.
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| 5. |
- Trompet, Dana, 1993, et al.
(författare)
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Stimulation of skeletal stem cells in the growth plate promotes linear bone growth
- 2024
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Ingår i: JCI INSIGHT. - 2379-3708. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1(fl/fl )tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling This opens therapeutic possibilities for the treatment of differences in leg length.
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| 6. |
- Chagin, Andrei S., 1976, et al.
(författare)
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Dual stem-cell populations interact in the skull
- 2023
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 621, s. 698-699
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Two types of stem cell produce similar progeny cells in the skull. [Figure not available: see fulltext.].
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| 7. |
- Chagin, Andrei S
(författare)
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Effect of estrogen on longitudinal bone growth
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Longitudinal bone growth occurs at the growth plate, a thin layer of cartilage between the epiphysis and the metaphysis of long bones. In the growth plate resting chondrocytes proliferate, differentiate into a hypertrophic form, and finally become terminal hypertrophic chondrocytes before giving rise to bone. Estrogen is essential for skeIetal growth. Extreme early puberty often leads to short stature, whereas significantly delayed puberty leads to increased final stature. Moreover, high doses of estrogen were used to prevent extreme tall stature in girls, but the treatment was associated with severe side effects. The effect of estrogen is mediated via two known estrogen receptors, ERalpha and ERbeta that are both expressed in growth plate chondrocytes. Although the effect of estrogen on bone growth is well known, the mechanism of action on longitudinal bone growth is poorly understood. We first studied longitudinal bone growth in female mice lacking ERalpha, ERbeta or both receptors (Paper I). Analysis of bone length and growth plate morphology revealed that ERbeta inhibits longitudinal bone growth. Moreover, in the presence of high serum concentrations of estrogen, stimulation of ERbeta induces growth plate fusion. Expression of both androgen and estrogen receptors were demonstrated within the growth plate. To study any co-interaction between estrogen and androgen receptors, we treated female ovariectomized rats with either estrogen, dihydrotestosterone (DHT) or the combination (Paper II). We found that estrogen inhibits longitudinal bone growth and growth plate height whereas DHT is able to counteract this effect. The effect is likely to be associated with systemic actions of these hormones since we found that decreased IGF-I levels in estrogen treated rats were restored by DHT. Estrogen regulates longitudinal bone growth either indirectly, via the modulation of the GH/IGF-I axis, or directly, via binding to estrogen receptors. Direct effects of estrogen were studied in a human chondrocytic cell line and in cultured fetal rat metatarsal bones (Paper III). We show that chondrocytes can synthesize estrogen by themselves and thereby mimic the effect of exogenous estrogen treatment. We also show that locally produced estrogen stimulates chondrocyte proliferation, inhibits apoptosis and maintains bone growth. Selective estrogen receptor modulators (SERMs) are promising drugs to modulate longitudinal growth offering fewer side-effects. We found that tamoxifen, a well known SERM, diminishes bone growth potential in cultured fetal rat metatarsal bones through selective apoptotic elimination of stem-like chondrocytes (Paper IV). Tamoxifen triggers the Fas/FasL apoptotic pathway and activates the caspases-8, -9 and 3. This thesis increases our understanding of how estrogen exerts its effect on longitudinal bone growth. This knowledge may be valuable for the development of new treatment strategies in children with growth disturbances, e.g. using SERMs to modulate the timing of growth plate fusion and thereby inhibit or stimulate the remaining growth potential.
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| 8. |
- Chagin, Andrei S., 1976, et al.
(författare)
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The Origin and Fate of Chondrocytes: Cell Plasticity in Physiological Setting
- 2023
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Ingår i: Current Osteoporosis Reports. - 1544-1873 .- 1544-2241. ; 21:6, s. 815-824
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Tidskriftsartikel (refereegranskat)abstract
- Purpose of ReviewHere, we discuss the origin of chondrocytes, their destiny, and their plasticity in relationship to bone growth, articulation, and formation of the trabeculae. We also consider these processes from a biological, clinical, and evolutionary perspective.Recent FindingsChondrocytes, which provide the template for the formation of most bones, are responsible for skeletal growth and articulation during postnatal life. In recent years our understanding of the fate of these cells has changed dramatically. Current evidence indicates a paradoxical situation during skeletogenesis, with some cells of mesenchymal condensation differentiating directly into osteoblasts, whereas others of the same kind give rise to highly similar osteoblasts via a complex process of differentiation involving several chondrocyte intermediates. The situation becomes even more paradoxical during postnatal growth when stem cells in the growth plate produce differentiated, functional progenies, which thereafter presumably dedifferentiate into another type of stem cell.SummarySuch a remarkable transition from one cell type to another under postnatal physiological conditions provides a fascinating example of cellular plasticity that may have valuable clinical implications.
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| 9. |
- Karimian, Elham, et al.
(författare)
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Tamoxifen impairs both longitudinal and cortical bone growth in young male rats.
- 2008
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 1523-4681. ; 23:8, s. 1267-77
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Tidskriftsartikel (refereegranskat)abstract
- Tamoxifen (Tam) has been used experimentally to treat boys with gynecomastia and girls with McCune-Albright syndrome. This drug was recently shown to inhibit the growth of cultured fetal rat metatarsal bones and thus might also affect bone growth in vivo. Four-week-old Sprague-Dawley rats were gavaged daily with vehicle alone (peanut oil), Tam (40 mg/kg/d; 1 or 4 wk), or estradiol (40 microg/kg/d; 4 wk). Five of the 10 rats in each group were killed after 4 wk and the other five after 14 wk of recovery. Bone growth was followed by repeat DXA scans, whereas other bone parameters and spine length were evaluated by pQCT and X-ray at the time of death. Four-week Tam treatment significantly decreased body weight, nose-anus distance, spinal and tibial bone lengths, trabecular BMD, cortical periosteal circumference, and bone strength and also reduced serum IGF-I levels (424 +/- 54 versus 606 +/- 53 ng/ml in control; p < 0.05). Analysis of the tibial growth plate of treated rats showed elevated chondrocyte proliferation (BrdU) and apoptosis (TUNEL), as well as decreases in the number of hypertrophic chondrocytes and in the size of terminal hypertrophic chondrocytes. Despite a complete catch-up of body weight after 14 wk of recovery, the tibia was still shorter (p < 0.001) and its cortical region was smaller. We conclude that, when administered at a clinically relevant dose, Tam causes persistent retardation of longitudinal and cortical radial bone growth in young male rats. Our findings suggest that this inhibition results from local effects on the growth plate cartilage and systemic suppression of IGF-I production. Based on these rat data, we believe that Tam, if given to growing individuals, might compromise cortical bone growth, bone strength, and adult height.
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| 10. |
- Kaucka, M., et al.
(författare)
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Altered developmental programs and oriented cell divisions lead to bulky bones during salamander limb regeneration
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- There are major differences in duration and scale at which limb development and regeneration proceed, raising the question to what extent regeneration is a recapitulation of development. We address this by analyzing skeletal elements using a combination of micro-CT imaging, molecular profiling and clonal cell tracing. We find that, in contrast to development, regenerative skeletal growth is accomplished based entirely on cartilage expansion prior to ossification, not limiting the transversal cartilage expansion and resulting in bulkier skeletal parts. The oriented extension of salamander cartilage and bone appear similar to the development of basicranial synchondroses in mammals, as we found no evidence for cartilage stem cell niches or growth plate-like structures during neither development nor regeneration. Both regenerative and developmental ossification in salamanders start from the cortical bone and proceeds inwards, showing the diversity of schemes for the synchrony of cortical and endochondral ossification among vertebrates. Normal limb development relies on synchronized formation of cartilage and bone. Here, the authors show that in salamander limb regeneration these processes are decoupled: ossification occurs after the final size of regenerating cartilage is reached, allowing fast regeneration and leading to bulky bones.
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