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| 2. |
- Chau, Michael, et al.
(författare)
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The synovial microenvironment suppresses chondrocyte hypertrophy and promotes articular chondrocyte differentiation
- 2022
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Ingår i: NPJ Regenerative medicine. - : Nature Publishing Group. - 2057-3995. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- During the development of the appendicular skeleton, the cartilaginous templates undergo hypertrophic differentiation and remodels into bone, except for the cartilage most adjacent to joint cavities where hypertrophic differentiation and endochondral bone formation are prevented, and chondrocytes instead form articular cartilage. The mechanisms that prevent hypertrophic differentiation and endochondral bone formation of the articular cartilage have not been elucidated. To explore the role of the synovial microenvironment in chondrocyte differentiation, osteochondral allografts consisting of articular cartilage, epiphyseal bone, and growth plate cartilage from distal femoral epiphyses of inbred Lewis rats expressing enhanced green fluorescent protein from a ubiquitous promoter were transplanted either in inverted or original (control) orientation to matching sites in wildtype littermates, thereby allowing for tracing of transplanted cells and their progenies. We found that no hypertrophic differentiation occurred in the growth plate cartilage ectopically placed at the joint surface. Instead, the transplanted growth plate cartilage, with time, remodeled into articular cartilage. This finding suggests that the microenvironment at the articular surface inhibits hypertrophic differentiation and supports articular cartilage formation. To explore this hypothesis, rat chondrocyte pellets were cultured with and without synoviocyte-conditioned media. Consistent with the hypothesis, hypertrophic differentiation was inhibited and expression of the articular surface marker lubricin (Prg4) was dramatically induced when chondrocyte pellets were exposed to synovium- or synoviocyte-conditioned media, but not to chondrocyte- or osteoblast-conditioned media. Taken together, we present evidence for a novel mechanism by which synoviocytes, through the secretion of a factor or factors, act directly on chondrocytes to inhibit hypertrophic differentiation and endochondral bone formation and promote articular cartilage formation. This mechanism may have important implications for articular cartilage development, maintenance, and regeneration.
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- Dou, Zelong, et al.
(författare)
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Rat perichondrium transplanted to articular cartilage defects forms articular-like, hyaline cartilage
- 2021
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Perichondrium autotransplants have been used to reconstruct articular surfaces destroyed by infection or trauma. However, the role of the transplanted perichondrium in the healing of resurfaced joints have not been investigated.DESIGN: Perichondrial and periosteal tissues were harvested from rats hemizygous for a ubiquitously expressed enhanced green fluorescent protein (EGFP) transgene and transplanted into full-thickness articular cartilage defects at the trochlear groove of distal femur in wild-type littermates. As an additional control, cartilage defects were left without a transplant (no transplant control). Distal femurs were collected 3, 14, 56, 112 days after surgery.RESULTS: Tracing of transplanted cells showed that both perichondrium and periosteum transplant-derived cells made up the large majority of the cells in the regenerated joint surfaces. Perichondrium transplants contained SOX9 positive cells and with time differentiated into a hyaline cartilage that expanded and filled out the defects with Col2a1-positive and Col1a1-negative chondrocytes and a matrix rich in proteoglycans. At later timepoints the cartilaginous perichondrium transplants were actively remodeled into bone at the transplant-bone interface and at post-surgery day 112 EGFP-positive perichondrium cells at the articular surface were positive for Prg4. Periosteum transplants initially lacked SOX9 expression and despite a transient increase in SOX9 expression and chondrogenic differentiation, remained Col1a1 positive, and were continuously thinning as periosteum-derived cells were incorporated into the subchondral compartment.CONCLUSIONS: Perichondrium and periosteum transplanted to articular cartilage defects did not just stimulate regeneration but were themselves transformed into cartilaginous articular surfaces. Perichondrium transplants developed into an articular-like, hyaline cartilage, whereas periosteum transplants appeared to produce a less resilient fibro-cartilage.
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- Gerver, Willem J. M., et al.
(författare)
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Arm Span and Its Relation to Height in a 2- to 17-Year-Old Reference Population and Heterozygous Carriers of ACAN Variants
- 2020
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 93:3, s. 164-172
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/OBJECTIVES: In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to serve as age references for clinical purposes; (2) to assess its age and sex dependency; and (3) to investigate relative AS adjustment for age and sex in individuals with ACAN haploinsufficiency.METHODS: The Maastricht study data (2,595 Caucasian children, 52% boys, 48% girls) were re-analysed to produce reference tables and graphs for age and sex of AS - H and AS/H. Published information on AS/H in Europeans was used as reference data for adults. Relative AS from 33 patients with ACAN haploinsufficiency were plotted against reference data and expressed as standard deviation score (SDS) for age and sex.RESULTS: Mean AS - H from 2 to 17 years increased from -1.2 to +1.5 cm in boys and from -4.8 to +1.6 cm in girls. Mean AS/H increased from 0.9848 to 1.0155 in boys and from 0.9468 to 1.0028 in girls. Mean AS/H in patients with ACAN haploinsufficiency was approximately 1.0, 1.5 and 0.5 SDS in young children, adolescents and 20- to 50-year-olds, respectively, and normal thereafter.CONCLUSIONS: These reference charts can be used for 2- to 17-year-old children/adolescents. Carriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.
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| 5. |
- Gkourogianni, Alexandra, et al.
(författare)
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Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant
- 2018
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 90:Suppl.1, s. 424-424
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (3shoulders, 10hands, 10wrists, 17spines, 10pelvis, 31hips, 79knees, 5 lower-legs, 4ankles, 4feet).Furthermore 2 computed tomography scans (1hip; 1knee), and 5 magnetic resonance scans (2hips; 3knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.Results: In the group of children (n=6; age ≤15yo; 3F:3M), six had moderately advanced BA (range:6-17.5months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also present-ed OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy.Among 16 adult patients (5F:11M), 16 had OCD (7elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40y) OA, (1shoulder, 5elbows, 3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs.Moreover 8 adult patients (3F:5M) have been operated, 4 pa-tients had hip replacement (1F:3M;3bilateral;1unilateral) and 5 knee arthroplasties (2F:3M; 3bilateral;2unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand x-rays and found no brachydactyly.Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height
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| 7. |
- Gkourogianni, Alexandra, et al.
(författare)
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Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Cary, USA : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 460-469
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Tidskriftsartikel (refereegranskat)abstract
- Context: Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, premature growth cessation and minor skeletal abnormalities.Objective: Characterize the phenotypic spectrum, associated conditions and response to growth-promoting therapies.Design: Retrospective international cohort study.Patients: Information from 103 individuals (57 female, 46 male) from 20 families with confirmed heterozygous ACAN mutations were included.Methods: Families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next generation sequencing, and/or Sanger sequencing. Clinical information was collected from medical records.Results: Identified ACAN variants showed perfect co-segregation with phenotype. Adult individuals had mildly disproportionate short stature (median height: -2.8 SDS, range: -5.9 to -0.9) and histories of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). There was no apparent genotype-phenotype correlation between type of ACAN mutation and presence of joint complaints. During childhood, height was less affected (median height: -2.0 SDS, range: -4.2 to -0.6). In contrast to most children with short stature, the majority of children had advanced BA (BA - CA, median: +1.3y; range +0.0 to +3.7y) reflecting a reduction in remaining growth potential. Nineteen individuals had received GH with some evidence of increased growth velocity.Conclusions Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. In several of the families, affected individuals developed early-onset osteoarthritis and degenerative disc disease requiring intervention, suggesting dysfunction of articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
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| 8. |
- Gkourogianni, Alexandra, et al.
(författare)
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Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment
- 2020
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell Publishing Inc.. - 0803-5253 .- 1651-2227. ; 109:10, s. 2067-2074
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To explore the phenotype and response to growth hormone in patients with heterozygous-mutations in the insulin-like growth factor I receptor gene (IGF1R).METHODS: Children with short-stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analyzed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation dependent probe amplification analysis.RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G>T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G>A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26 - 0.60) and 0.64 (range: 0.32 - 0.86) after 1 and 2 years of treatment, respectively.CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.
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| 9. |
- Tatsi, Christina, et al.
(författare)
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Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation
- 2017
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 1:8, s. 1006-1011
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Tidskriftsartikel (refereegranskat)abstract
- Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in ACAN, the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a de novo novel heterozygous frameshift mutation in ACAN (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in ACAN (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with ACAN mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous ACAN mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation.
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