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- Pekkinen, M., et al.
(författare)
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Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2
- 2019
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Ingår i: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 4:7
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated 6 families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.IIe62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.IIe62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasial Several subjects had experienced peripheral facial nerve palsy or other neurological manifestations. Bone biopsies showed markedly altered bone material characteristics, including defective bone mineralization. Osteoclast formation and function in vitro was normal. While the p.Arg50* mutation yielded a catalytically inactive enzyme, p.IIe62Ser and p.Met64Arg each enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. SGMS2 pathogenic variants underlie a spectrum of skeletal conditions, ranging from isolated osteoporosis to complex skeletal dysplasia, suggesting a critical role for plasma membrane-bound sphingomyelin metabolism in skeletal homeostasis.
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| 5. |
- Tamminen, Inari S., et al.
(författare)
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Increased Heterogeneity of Bone Matrix Mineralization in Pediatric Patients Prone to Fractures: A Biopsy Study
- 2014
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 29:5, s. 1110-1117
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic osteoporosis (IOP) in children is characterized by fragility fractures and/or low bone mineral density in otherwise healthy individuals. The aim of the present work was to measure bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) in children with suspected IOP. Entire cross-sectional areas of transiliac bone biopsy samples from children (n=24, 17 boys; aged 6.7-16.6 years) with a history of fractures (n=14 with at least one vertebral fracture) were analyzed for cancellous (Cn) and cortical (Ct) BMDD. Outcomes were compared with normal reference BMDD data and correlated with the patients' clinical characteristics and bone histomorphometry findings. The subjects had similar average degree but significantly higher heterogeneity of mineralization in both Cn and Ct bone (Cn.CaWidth +23%, Ct.CaWidth +15%, p<0.001 and p=0.002, respectively), together with higher percentages of low mineralized cancellous (Cn.CaLow +35%, p<0.001) and highly mineralized cortical bone areas (Ct.CaHigh +82%, p=0.032). Ct.CaWidth and Ct.CaLow were positively correlated with mineralizing surface per bone surface (MS/BS; a primary histomorphometric determinant of bone formation) and with serum bone turnover markers (all p<0.05). The correlations of the mineralization heterogeneity with histomorphometric and serum bone turnover indices suggest that an enhanced variation in bone turnover/formation contributes to the increased heterogeneity of mineralization. However, it remains unclear whether the latter is cause for, or the response to the increased bone fragility in these children with suspected IOP. (c) 2014 American Society for Bone and Mineral Research.
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| 6. |
- van der Eerden, B. C. J., et al.
(författare)
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TRPV4 deficiency causes sexual dimorphism in bone metabolism and osteoporotic fracture risk
- 2013
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 57:2, s. 443-454
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Tidskriftsartikel (refereegranskat)abstract
- We explored the role of transient receptor potential vanilloid 4 (TRPV4) in murine bone metabolism and association of TRPV4 gene variants with fractures in humans. Urinary and histomorphometrical analyses demonstrated reduced osteoclast activity and numbers in male Trpv4(-/-) mice, which was confirmed in bone marrow-derived osteoclast cultures. Osteoblasts and bone formation as shown by serum procollagen type 1 amino-terminal propeptide and histomorphometry, including osteoid surface, osteoblast and osteocyte numbers were not affected in vivo. Nevertheless, osteoblast differentiation was enhanced in Trpv4(-/-) bone marrow cultures. Cortical and trabecular bone mass was 20% increased in male Trpv4(-/-) mice, compared to sex-matched wild type (Trpv4(+/+)) mice. However, at the same time intracortical porosity was increased and bone matrix mineralization was reduced. Together, these lead to a maximum load, stiffness and work to failure of the femoral bone, which were not different compared to Trpv4(+/+) mice, while the bone material was less resistant to stress and less elastic. The differential impacts on these determinants of bone strength were likely responsible for the lack of any changes in whole bone strength in the Trpv4(-/-) mice. None of these skeletal parameters were affected in female Trpv4(-/-) mice. The T-allele of rs1861809 SNP in the TRPV4 locus was associated with a 30% increased risk (95% Cl: 1.1-1.6; p = 0.013) for non-vertebral fracture risk in men, but not in women, in the Rotterdam Study. Meta-analyses with the population-based LASA study confirmed the association with non-vertebral fractures in men. This was lost when the non-population-based studies Mr. OS and UFO were included. In conclusion, TRPV4 is a male-specific regulator of bone metabolism, a determinant of bone strength, and a potential risk predictor for fractures through regulation of bone matrix mineralization and intra-cortical porosity. This identifies TRPV4 as a unique sexually dimorphic therapeutic and/or diagnostic candidate for osteoporosis. C) 2013 Elsevier Inc. All rights reserved.
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