Abnormal Proteoglycan Synthesis Due to Gene Defects Causes Skeletal Diseases with Overlapping Phenotypes

Taylan, Fulya; Mäkitie, Outi

doi:10.1055/s-0042-118706

Cited by 24 publications

(29 citation statements)

References 56 publications

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“…PGs-especially heparan sulfate and chondroitin sulfate that are abundant on the cell surface and in chondrocyte extracellular matrix (ECM)-create a microenvironment for diverse cellular processes such as signaling, cell adhesion, proliferation, differentiation, and motility. They also play a role in chondrocyte maturation and endochondral skeletal development [42].…”

Section: Xylt2 Osteoporosismentioning

confidence: 99%

Recent Discoveries in Monogenic Disorders of Childhood Bone Fragility

Mäkitie

Kämpe

Taylan

et al. 2017

Curr Osteoporos Rep

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Advances in genetic research, particularly next-generation sequencing, have found several genetic loci that associate with monogenic forms of inherited osteoporosis, widening the scope of primary osteoporosis beyond classical osteogenesis imperfecta. New forms of primary osteoporosis, such as those related to WNT1, PLS3, and XYLT2, have identified defects outside the extracellular matrix components and collagen-related pathways, in intracellular cascades directly affecting bone cell function. Primary osteoporosis can lead to severe skeletal morbidity, including abnormal longitudinal growth, compromised bone mass gain, and noticeable fracture tendency beginning at childhood. Early diagnosis and timely care are warranted to ensure the best achievable bone health. Future research will most likely broaden the spectrum of primary osteoporosis, hopefully provide more insight into the genetics governing bone health, and offer new targets for treatment.

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Section: Xylt2 Osteoporosismentioning

confidence: 99%

Recent Discoveries in Monogenic Disorders of Childhood Bone Fragility

Mäkitie

Kämpe

Taylan

et al. 2017

Curr Osteoporos Rep

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“…Gene defects in several human enzymes participating in GAG synthesis, among them xylosyltransferases 1 and 2, and at least two galactosyltransferases, are held responsible for several uncommon disorders affecting skeletal and joint structures (43). A defect in B3GALT6 (encoding for β-1l3-Galactosyltransferase-II) is tied to the progeroid type of Ehlers-Danlos syndrome (44).…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

Haythorn¹,

Young²,

Stanton³

et al. 2020

Preprint

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Background Equine Degenerative Suspensory Desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses, but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments leads to progressive and debilitating lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous studies suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken. Methods Next generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 Warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined False Discovery Rates derived from the P-values adjusted for multiple testing for any given result. Results Bioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (most prominently BMP2, FGF5, CTGF, members of the EGF family), of mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were also overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens and many peptides with immune function. Conclusions The overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2 , and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.

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“…Research focuses on the topics of bone formation, growth, and repair [1][2][3][4][5][6][7][8][9][10]. This is a timely collection of articles, as our understanding of these topics has advanced significantly in the last decade.…”

Section: This Special Issue Of Hormone and Metabolicmentioning

confidence: 99%

“…After all, many of the key roles of the skeleton, support, movement, and protection, are to a large extent made possible by the massive mineralized extracellular matrix that is bone. Taylan et al provide insight on this important feature of bone in their report on the important role of proteoglycans in bone health disease [6].…”

mentioning

confidence: 99%