Strengths and opportunities in research into extracellular matrix ageing: A consultation with the ECMage research community.

Ageing causes progressive decline in metabolic, behavioural, and physiological functions, leading to a reduced health span. The extracellular matrix (ECM) is the three-dimensional network of macromolecules that provides our tissues with structure and biomechanical resilience. Imbalance between damage and repair/regeneration causes the ECM to undergo structural deterioration with age, contributing to age-associated pathology.

Multimodal analysis of the differential effects of cyclic strain on collagen isoform composition, fibril architecture and biomechanics of tissue engineered tendon.

Tendon is predominantly composed of aligned type I collagen, but additional isoforms are known to influence fibril architecture and maturation, which contribute to the tendon's overall biomechanical performance. The role of the less well-studied collagen isoforms on fibrillogenesis in tissue engineered tendons is currently unknown, and correlating their relative abundance with biomechanical changes in response to cyclic strain is a promising method for characterising optimised bioengineered tendon grafts. In this study, human mesenchymal stem cells (MSCs) were cultured in a fibrin scaffold with 3%, 5% or 10% cyclic strain at 0.

Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.

The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the first time, that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However, Mendelian inheritance was affected in male mice of both lines, and male mice null for the α2(I) chain exhibited age-related loss of condition.

Intrafascicular chondroid-like bodies in the ageing equine superficial digital flexor tendon comprise glycosaminoglycans and type II collagen.

The superficial digital flexor tendon (SDFT) is considered functionally equivalent to the human Achilles tendon. Circular chondroid depositions scattered amongst the fascicles of the equine SDFT are rarely reported. The purpose of this study was the detailed characterization of intrafascicular chondroid-like bodies (ICBs) in the equine SDFT, and the assessment of the effect of ageing on the presence and distribution of these structures.

Identification and Characterization of Canine Ligament Progenitor Cells and Their Extracellular Matrix Niche.

Ligaments are prone to injury and degeneration in humans and animals, however the healing potential of ligament is poor and current treatment options ineffective. Stem cell-based therapies hold potential for treatment of ligament injuries. This study aimed to characterize a ligament progenitor cell (LPC) population and to identify specific niche components which could promote the survival and function of LPCs.

A comparison of the stem cell characteristics of murine tenocytes and tendon-derived stem cells.

Tendon is a commonly injured soft musculoskeletal tissue, however, poor healing potential and ineffective treatment strategies result in persistent injuries and tissue that is unable to perform its normal physiological function. The identification of a stem cell population within tendon tissue holds therapeutic potential for treatment of tendon injuries. This study aimed, for the first time, to characterise and compare tenocyte and tendon-derived stem cell (TDSC) populations in murine tendon.

Variations in internal structure, composition and protein distribution between intra- and extra-articular knee ligaments and tendons.

Tendons and ligaments play key roles in the musculoskeletal system in both man and animals. Both tissues can undergo traumatic injury, age-related degeneration and chronic disease, causing discomfort, pain and increased susceptibility to wider degenerative joint disease. To date, tendon and ligament ultrastructural biology is relatively under-studied in healthy, non-diseased tissues.

Ligament-Derived Stem Cells: Identification, Characterisation, and Therapeutic Application.

Ligament is prone to injury and degeneration and has poor healing potential and, with currently ineffective treatment strategies, stem cell therapies may provide an exciting new treatment option. Ligament-derived stem cell (LDSC) populations have been isolated from a number of different ligament types with the majority of studies focussing on periodontal ligament. To date, only a few studies have investigated LDSC populations in other types of ligament, for example, intra-articular ligaments; however, this now appears to be a developing field.

Proteomic differences between native and tissue-engineered tendon and ligament.

Tendons and ligaments (T/Ls) play key roles in the musculoskeletal system, but they are susceptible to traumatic or age-related rupture, leading to severe morbidity as well as increased susceptibility to degenerative joint diseases such as osteoarthritis. Tissue engineering represents an attractive therapeutic approach to treating T/L injury but it is hampered by our poor understanding of the defining characteristics of the two tissues. The present study aimed to determine differences in the proteomic profile between native T/Ls and tissue engineered (TE) T/L constructs.

Matrix metalloproteinase 14 is required for fibrous tissue expansion.

Type I collagen-containing fibrils are major structural components of the extracellular matrix of vertebrate tissues, especially tendon, but how they are formed is not fully understood. MMP14 is a potent pericellular collagenase that can cleave type I collagen in vitro. In this study, we show that tendon development is arrested in Scleraxis-Cre::Mmp14 lox/lox mice that are unable to release collagen fibrils from plasma membrane fibripositors.

Chick tendon fibroblast transcriptome and shape depend on whether the cell has made its own collagen matrix.

Collagen- and fibrin-based gels are extensively used to study cell behaviour. However, 2D-3D and collagen-fibrin comparisons of gene expression, cell shape and mechanotransduction, with an in vivo reference, have not been reported. Here we compared chick tendon fibroblasts (CTFs) at three stages of embryonic development with CTFs cultured in collagen- or fibrin-based tissue engineered constructs (TECs).

Restricted differentiation potential of progenitor cell populations obtained from the equine superficial digital flexor tendon (SDFT).

The aim of this study was to characterize stem and progenitor cell populations from the equine superficial digital flexor tendon, an energy-storing tendon with similarities to the human Achilles tendon, which is frequently injured. Using published methods for the isolation of tendon-derived stem/progenitor cells by low-density plating we found that isolated cells possessed clonogenicity but were unable to fully differentiate towards mesenchymal lineages using trilineage differentiation assays. In particular, adipogenic differentiation appeared to be restricted, as assessed by Oil Red O staining of stem/progenitor cells cultured in adipogenic medium.

Stepwise proteolytic activation of type I procollagen to collagen within the secretory pathway of tendon fibroblasts in situ.

Proteolytic cleavage of procollagen I to collagen I is essential for the formation of collagen fibrils in the extracellular matrix of vertebrate tissues. Procollagen is cleaved by the procollagen N- and C-proteinases, which remove the respective N- and C-propeptides from procollagen. Procollagen processing is initiated within the secretory pathway in tendon fibroblasts, which are adept in assembling an ordered extracellular matrix of collagen fibrils in vivo.

Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation.

GDF5 is involved in synovial joint development, maintenance and repair, and the rs143383 C/T single nucleotide polymorphism (SNP) located in the 5'UTR of GDF5 is associated, at the genome-wide significance level, with osteoarthritis susceptibility, and with other musculoskeletal phenotypes including height, congenital hip dysplasia and Achilles tendinopathy. There is a significant reduction in the expression of the disease-associated T allele relative to the C allele in synovial joint tissues, an effect influenced by a second SNP (rs143384, C/T) also within the 5'UTR. The differential allelic expression (DAE) imbalance of the C and T alleles of rs143383 varies intra- and inter-individually, suggesting that DAE may be modulated epigenetically.

An experimental model for studying the biomechanics of embryonic tendon: Evidence that the development of mechanical properties depends on the actinomyosin machinery.

Tendons attach muscles to bone and thereby transmit tensile forces during joint movement. However, a detailed understanding of the mechanisms that establish the mechanical properties of tendon has remained elusive because of the practical difficulties of studying tissue mechanics in vivo. Here we have performed a study of tendon-like constructs made by culturing embryonic tendon cells in fixed-length fibrin gels.

Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid.

The bone morphogenetic protein (BMP)-1/tolloid metalloproteinases are evolutionarily conserved enzymes that are fundamental to dorsal-ventral patterning and tissue morphogenesis. The lack of knowledge regarding how these proteinases recognize and cleave their substrates represents a major hurdle to understanding tissue assembly and embryonic patterning. Although BMP-1 and mammalian tolloid (mTLD) are splice variants, it is puzzling why BMP-1, which lacks 3 of the 7 noncatalytic domains present in all other family members, is the most effective proteinase.

Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators.

Collagens are triple helical proteins that occur in the extracellular matrix (ECM) and at the cell-ECM interface. There are more than 30 collagens and collagen-related proteins but the most abundant are collagens I and II that exist as D-periodic (where D = 67 nm) fibrils. The fibrils are of broad biomedical importance and have central roles in embryogenesis, arthritis, tissue repair, fibrosis, tumor invasion, and cardiovascular disease.