Loss of scleraxis in mice leads to geometric and structural changes in cortical bone, as well as asymmetry in fracture healing

More than 250 years ago, William Hunter stated that when cartilage is destroyed it never recovers. In the last 20 years, the understanding of the mechanisms that lead to joint formation and the knowledge that some of these mechanisms are reactivated in the homeostatic responses of cartilage to injury has offered an unprecedented therapeutic opportunity to achieve cartilage regeneration. Very large investments in ambitious clinical trials are finally revealing that, although we do not have perfect medicines yet, disease modification is a feasible possibility for human osteoarthritis.

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“…166 The Scx+Sox9+ lineage persist in the adult enthesis and periosteum 164 and contribute to tendon and fracture healing. 164,[168][169][170]…”

Section: Scx+sox9+ Progenitorsmentioning

confidence: 99%

Lessons from joint development for cartilage repair in the clinic

Thorup

Dell’Accio

Eldridge

2020

Developmental Dynamics

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“…For example, with developments in molecular biology, an increasing number of genes and biological processes have been found to be associated with fracture healing, and the subsequent emergence of corresponding small bioactive molecules may assist in the treatment of fracture nonunion. Previous evidence suggests that Scx may be involved in the periosteal response during fracture healing ( 3 ). Fischerauer et al ( 4 ) demonstrated that bone morphogenetic protein receptor, type IA (BMPR1A) was upregulated in the growth plate of the fractured tibia, and Morgan et al ( 5 ) found that a BMPR1Aantagonist affected cartilage and bone formation during fracture healing.…”

Section: Introductionmentioning

confidence: 99%

Time-series expression profile analysis of fracture healing in young and old mice

Yuan

Cai

2017

Molecular Medicine Reports

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Bone fracture healing is a complex process, which is associated with several factors, including age and osteoporosis. Certain genes and biological processes that may contribute to fracture healing, have been identified following developments in systems biology and molecular biology technologies, which may benefit the treatment of bone fractures. The present study identified key genes, which may be important in fracture healing through bioinformatics analysis of gene microarray datasets from the Gene Expression Omnibus. Gene clusters, which were consistently up/downregulated through time following a fracture in young (6-week-old) mice and old (8-month-old retired breeders) mice were obtained via soft clustering of differentially expressed genes (DEGs) between samples at 1 and 3 days, 1 and 5 days, and 3 and 5 days post-fracture in the two age groups, based on the Mfuzz package of R. Functional enrichment analysis of gene clusters using the Database for Annotation, Visualization and Integrated Discovery indicated that biological processes and pathways, including those associated with bone development, skeletal system development, amino sugar and nucleotide sugar metabolism, were significantly enriched in these up/downregulated genes. Of note, a total of 207 overlapped consistently upregulated genes were obtained between the two age groups, whereas no overlap was identified between the two lists of consistently downregulated genes. The overlapped genes were found to be associated with the biological processes of blood vessel development, vasculature development and skeletal system development, compared with all genes in the clusters. In addition, certain genes, including epidermal growth factor-like domain multiple 6 (EGFL6), kazal-type serine peptidase inhibitor domain 1 (KAZALD1), olfactomedin 2B (OLFM2B), collagen type III α1 (COL3A1), collagen type II α1 (COL2A1), von Willebrand factor A domain-containing 1 (VWA1), elastin microfibril interfacer 1 (EMILIN1) and aggrecan (ACAN), of the extracellular matrix organization, a process performed at the cellular level and resulting in the assembly and arrangement of constituent parts, were confirmed to be associated with fracture healing via reverse transcription-quantitative polymerase chain reaction analysis. The present study identified certain genes and biological processes/pathways, which may be associated with fracture healing and may assist in fundamental investigations and treatment in the future.

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“…Scleraxis (Scx), a member of the Twist-family of basic helix-loop-helix (HLH) transcription factors, is required for tenogenesis. This factor is shown to be critical for the development of functional tendons because it regulates tenocyte specific factors such as tenomodulin (Tnmd) and proteoglycans [33][34][35]. Scx directly transactivates Tnmd via preferential binding to specific DNA sequences via E-boxes such as SCX/E12 or SCX/E47 heterodimers [36].…”

Section: The Impact Of Mechanical Loadingmentioning

confidence: 99%

Impact of Uniaxial Stretching on Both Gliding and Traction Areas of Tendon Explants in a Novel Bioreactor

Tohidnezhad

Zander

Slowik

et al. 2020

IJMS

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The effects of mechanical stress on cells and their extracellular matrix, especially in gliding sections of tendon, are still poorly understood. This study sought to compare the effects of uniaxial stretching on both gliding and traction areas in the same tendon. Flexor digitorum longus muscle tendons explanted from rats were subjected to stretching in a bioreactor for 6, 24, or 48 h, respectively, at 1 Hz and an amplitude of 2.5%. After stimulation, marker expression was quantified by histological and immunohistochemical staining in both gliding and traction areas. We observed a heightened intensity of scleraxis after 6 and 24 h of stimulation in both tendon types, though it had declined again 48 h after stimulation. We observed induced matrix metalloproteinase-1 and -13 protein expression in both tendon types. The bioreactor produced an increase in the mechanical structural strength of the tendon during the first half of the loading time and a decrease during the latter half. Uniaxial stretching of flexor tendon in our set-up can serve as an overloading model. A combination of mechanical and histological data allows us to improve the conditions for cultivating tendon tissues.

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Loss of scleraxis in mice leads to geometric and structural changes in cortical bone, as well as asymmetry in fracture healing

Cited by 14 publications

References 52 publications

Lessons from joint development for cartilage repair in the clinic

Lessons from joint development for cartilage repair in the clinic

Time-series expression profile analysis of fracture healing in young and old mice

Impact of Uniaxial Stretching on Both Gliding and Traction Areas of Tendon Explants in a Novel Bioreactor

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