| 1. |
- Kurenkova, A. D., et al.
(författare)
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Notch Signaling Regulates the Chondrogenic Potential of Both Articular Chondrocytes and Their Progenitors During Expansion
- 2023
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Ingår i: Stem Cells. - 1066-5099. ; 41:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Articular cartilage has a limited capacity for self-repair and clinical approaches to cartilage regeneration are needed. The only such approach developed to date involves an expansion of primary autologous chondrocytes in culture, followed by their reimplantation into a cartilage defect. However, because of the formation of fibrocartilage instead of hyaline cartilage, the outcome is often not satisfactory. It happens due to the de-differentiation of chondrocytes during the expansion step. Indeed, articular chondrocytes are non-proliferative and require partial or complete dedifferentiation before actively proliferating. In recent years stem/progenitor cells in articular cartilage (artSPCs) have been described. These cells maintain their own population and renew articular cartilage in sexually mature mice. artSPCs can, theoretically, be superior to chondrocytes, for repairing damaged cartilage. Accordingly, here, we searched for conditions that allow rapid expansion of both artSPCs and chondrocytes with simultaneous preservation of their ability to form hyaline cartilage. Among the modulators of Wnt, Notch, and FGF signaling and of cell adhesion screened, only fibronectin and modulators of the Notch pathway promoted the rapid expansion of artSPCs. Surprisingly, both inhibition and activation of the pathway had this effect. However, only inhibition of Notch during expansion facilitated the chondrogenic potential of both artSPCs and primary chondrocytes, whereas activation of this pathway abrogated this potential entirely. This effect was the same for murine and human cells. Our present observations indicate that Notch signaling is the major regulator of the chondrogenic capacity of both artSPCs and chondrocytes during their expansion.
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| 2. |
- Moverare-Skrtic, Sofia, et al.
(författare)
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B4GALNT3 regulates glycosylation of sclerostin and bone mass
- 2023
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Ingår i: eBioMedicine. - 2352-3964. ; 91
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Tidskriftsartikel (refereegranskat)abstract
- Background Global sclerostin inhibition reduces fracture risk efficiently but has been associated with cardiovascular side effects. The strongest genetic signal for circulating sclerostin is in the B4GALNT3 gene region, but the causal gene is unknown. B4GALNT3 expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3 that transfers N-acetylgalactosamine onto N-acetylglucosaminebeta-benzyl on protein epitopes (LDN-glycosylation). Methods To determine if B4GALNT3 is the causal gene, B4galnt3 / mice were developed and serum levels of total sclerostin and LDN-glycosylated sclerostin were analysed and mechanistic studies were performed in osteoblast-like cells. Mendelian randomization was used to determine causal associations. Findings B4galnt3 / mice had higher circulating sclerostin levels, establishing B4GALNT3 as a causal gene for circulating sclerostin levels, and lower bone mass. However, serum levels of LDN-glycosylated sclerostin were lower in B4galnt3 / mice. B4galnt3 and Sost were co-expressed in osteoblast-lineage cells. Overexpression of B4GALNT3 increased while silencing of B4GALNT3 decreased the levels of LDN-glycosylated sclerostin in osteoblast-like cells. Mendelian randomization demonstrated that higher circulating sclerostin levels, genetically predicted by variants in the B4GALNT3 gene, were causally associated with lower BMD and higher risk of fractures but not with higher risk of myocardial infarction or stroke. Glucocorticoid treatment reduced B4galnt3 expression in bone and increased circulating sclerostin levels and this may contribute to the observed glucocorticoid-induced bone loss. Interpretation B4GALNT3 is a key factor for bone physiology via regulation of LDN-glycosylation of sclerostin. We propose that B4GALNT3-mediated LDN-glycosylation of sclerostin may be a bone-specific osteoporosis target, separating the anti-fracture effect of global sclerostin inhibition, from indicated cardiovascular side effects. Funding Found in acknowledgements.
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| 3. |
- Nethander, Maria, 1980, et al.
(författare)
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An atlas of genetic determinants of forearm fracture.
- 2023
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Ingår i: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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