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Research Progress on Molecular Repair of Tendon/Ligament

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 26374

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Prof. Dr. Emerito Carlos Rodriguez-Merchan

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Guest Editor

Department of Orthopedic Surgery, La Paz University Hospital, 28046 Madrid, Spain
Interests: orthopedic surgery; joint replacement; knee surgery; hemophilic arthropathy
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Dear Colleagues,

Tendon and ligament injuries represent the most common musculoskeletal complaints for which patients seek medical attention. Additionally, they are common in either the workplace or sport activities, with some 3 to 5 million tendon and ligament injuries happening yearly worldwide.

Current therapeutic alternatives for addressing tendon and ligament injuries are frequently inefficacious, and the need for improved understanding of tendon physiology is paramount. Management of tendon and ligament injuries currently follows two ways: conservative (rehabilitation and pain relief) or surgical. Irrespective of which of these primary treatment ways is followed, even if healing does happen, it might not result in a full recovery of function. The inability of the tendon to self-repair and the relative inefficiency of current treatment regimens suggest that identifying alternative strategies is crucial.

The repair of tendon injuries still presents a major clinical challenge to orthopedic medicine. Tendons and ligaments are poorly vascularized and heal slowly. Further, healing often causes the formation of fibrous tissue and scar tissue which lack flexibility and biomechanical properties. Thus, the management of tendon and ligament injuries is challenging.

For this reason, better knowledge of the molecular mechanisms underlying tendon and ligament healing is fundamental for the development of new treatments to accelerate it. These include platelet-rich plasma (PRP), which has been shown effective in treating many tendon and ligament disorders; synthetic peptides to endow biomaterials with novel biological functions, namely to capture and immobilize endogenous growth factors; hydrogel-mediated delivery of bone morphogenetic protein-2 (BMP-2) and GSK126 that appears to be safe and has the potential to enhance tendon-to-bone tunnel healing in ligament reconstructions; engineered tissue graft for rotator cuff in rotator cuff tears; and combined stem cell technology with a non-absorbable biomaterial for the reconstruction of the ruptured anterior cruciate ligament.

Prof. Dr. Emerito Carlos Rodriguez-Merchan
Guest Editor

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Keywords

tendon
ligament
repair
molecular basis

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Published Papers (7 papers)

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Research

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16 pages, 5446 KiB

Open AccessArticle

Multiparity and Aging Impact Chondrogenic and Osteogenic Potential at Symphyseal Enthesis: New Insights into Interpubic Joint Remodeling

by Lizandra Maia de Sousa, Bianca Gazieri Castelucci, Paula Andrea Saenz Suarez, Ingrid Iara Damas, Fernanda Viviane Mariano, Paulo Pinto Joazeiro and Sílvio Roberto Consonni

Int. J. Mol. Sci. 2023, 24(5), 4573; https://doi.org/10.3390/ijms24054573 - 26 Feb 2023

Viewed by 2243

Abstract

Pregnancy and childbirth cause adaptations to the birth canal to allow for delivery and fast recovery. To accommodate delivery through the birth canal, the pubic symphysis undergoes changes that lead to the interpubic ligament (IpL) and enthesis formation in primiparous mice. However, successive deliveries influence joint recovery. We aimed to understand tissue morphology and chondrogenic and osteogenic potential at symphyseal enthesis during pregnancy and postpartum in primiparous and multiparous senescent female mice. Morphological and molecular differences were found at the symphyseal enthesis among the study groups. Despite the apparent incapacity to restore cartilage in multiparous senescent animals, the symphyseal enthesis cells are active. However, these cells have reduced expression of chondrogenic and osteogenic markers and are immersed in densely packed collagen fibers contiguous to the persistent IpL. These findings may indicate alterations of key molecules in the progenitor cell population maintenance of the chondrocytic and osteogenic lineages at the symphyseal enthesis in multiparous senescent animals, possibly compromising the mouse joint histoarchitecture recovery. This sheds light on the distention of the birth canal and the pelvic floor that may play a role in pubic symphysis diastasis (PSD) and pelvic organ prolapse (POP), both in orthopedic and urogynecological practice in women. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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17 pages, 2425 KiB

Open AccessArticle

Platelet-Derived Extracellular Vesicles Promote Tenogenic Differentiation of Stem Cells on Bioengineered Living Fibers

by Ana L. Graça, Rui M. A. Domingues, Manuel Gomez-Florit and Manuela E. Gomes

Int. J. Mol. Sci. 2023, 24(4), 3516; https://doi.org/10.3390/ijms24043516 - 9 Feb 2023

Cited by 9 | Viewed by 2867

Abstract

Tendon mimetic scaffolds that recreate the tendon hierarchical structure and niche have increasing potential to fully restore tendon functionality. However, most scaffolds lack biofunctionality to boost the tenogenic differentiation of stem cells. In this study, we assessed the role of platelet-derived extracellular vesicles (EVs) in stem cells’ tenogenic commitment using a 3D bioengineered in vitro tendon model. First, we relied on fibrous scaffolds coated with collagen hydrogels encapsulating human adipose-derived stem cells (hASCs) to bioengineer our composite living fibers. We found that the hASCs in our fibers showed high elongation and cytoskeleton anisotropic organization, typical of tenocytes. Moreover, acting as biological cues, platelet-derived EVs boosted the hASCs’ tenogenic commitment, prevented phenotypic drift, enhanced the deposition of the tendon-like extracellular matrix, and induced lower collagen matrix contraction. In conclusion, our living fibers provided an in vitro system for tendon tissue engineering, allowing us to study not only the tendon microenvironment but also the influence of biochemical cues on stem cell behavior. More importantly, we showed that platelet-derived EVs are a promising biochemical tool for tissue engineering and regenerative medicine applications that are worthy of further exploration, as paracrine signaling might potentiate tendon repair and regeneration. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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10 pages, 1992 KiB

Open AccessArticle

Degraded RNA from Human Anterior Cruciate Ligaments Yields Valid Gene Expression Profiles

by Megan N. Ashton, Asha E. Worsham, Matthew D. Strawn, Geoffrey D. Fisher, Cody J. Perry, Matthew P. Ferguson, Mimi Zumwalt, George W. Brindley, Javad Hashemi, Hossein Mansouri, James R. Slauterbeck and Daniel M. Hardy

Int. J. Mol. Sci. 2023, 24(3), 1895; https://doi.org/10.3390/ijms24031895 - 18 Jan 2023

Cited by 1 | Viewed by 2831

Abstract

Correlating gene expression patterns with biomechanical properties of connective tissues provides insights into the molecular processes underlying the tissue growth and repair. Cadaveric specimens such as human knees are widely considered suitable for biomechanical studies, but their usefulness for gene expression experiments is potentially limited by the unavoidable, nuclease-mediated degradation of RNA. Here, we tested whether valid gene expression profiles can be obtained using degraded RNA from human anterior cruciate ligaments (ACLs). Human ACL RNA (N = 6) degraded in vitro by limited ribonuclease digestion resemble highly degraded RNA isolated from cadaveric tissue. PCR threshold cycle (C_t) values for 90 transcripts (84 extracellular matrix, 6 housekeeping) in degraded RNAs variably ranged higher than values obtained from their corresponding non-degraded RNAs, reflecting both the expected loss of target templates in the degraded preparations as well as differences in the extent of degradation. Relative C_t values obtained for mRNAs in degraded preparations strongly correlated with the corresponding levels in non-degraded RNA, both for each ACL as well as for the pooled results from all six ACLs. Nuclease-mediated degradation produced similar, strongly correlated losses of housekeeping and non-housekeeping gene mRNAs. RNA degraded in situ yielded comparable results, confirming that in vitro digestion effectively modeled degradation by endogenous ribonucleases in frozen and thawed ACL. We conclude that, contrary to conventional wisdom, PCR-based expression analyses can yield valid mRNA profiles even from RNA preparations that are more than 90% degraded, such as those obtained from connective tissues subjected to biomechanical studies. Furthermore, legitimate quantitative comparisons between variably degraded tissues can be made by normalizing data to appropriate housekeeping transcripts. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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12 pages, 5567 KiB

Open AccessArticle

Tendon-Specific Activation of Tenogenic Transcription Factors Enables Keeping Tenocytes’ Identity In Vitro

by Rui Chen and Thomas Skutella

Int. J. Mol. Sci. 2022, 23(22), 14078; https://doi.org/10.3390/ijms232214078 - 15 Nov 2022

Viewed by 2190

Abstract

We generated a novel tetracycline-inducible transgenic mouse line with the tendon-specific expression of a series of tendon-critical transcription factors. Primary tenocytes derived from this mouse line consistently expressed green fluorescent protein reporter transcription factors in response to doxycycline. The tenocytes maintained their tendon cell properties for a longer time after the transient induction in the absence of growth factors and mechanical stress. Four key transcription factors for tendon development and the green fluorescent protein reporter were linked with different viral 2A self-cleaving peptides. They were expressed under the control of the tet-responsive element. In combination with the expression of BFP, which reports on the tendon-specific collagen I, and mScarlet, which reports on the tendon-specific transcription factor Scleraxis (Scx), we observed the more extended maintenance of the tendon cell identity of in vitro cultured tendon cells and Achilles tendon explants. This means that the Scleraxis bHLH transcription factor (Scx), mohawk homeobox (Mkx), early growth response 1 (Egr1) and early growth response 2 (Egr2) contributed to the maintenance of tenocytes’ identity in vitro, providing a new model for studying extracellular matrix alterations and identifying alternative biomaterials in vitro. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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11 pages, 3825 KiB

Open AccessArticle

Apoptotic Body-Rich Media from Tenocytes Enhance Proliferation and Migration of Tenocytes and Bone Marrow Stromal Cells

by Chenhui Dong, Anne Gingery, Peter C. Amadio, Kai-Nan An, Steven L. Moran and Chunfeng Zhao

Int. J. Mol. Sci. 2022, 23(19), 11475; https://doi.org/10.3390/ijms231911475 - 29 Sep 2022

Cited by 5 | Viewed by 2091

Abstract

The intrinsic healing following tendon injury is ideal, in which tendon progenitor cells proliferate and migrate to the injury site to directly bridge or regenerate tendon tissue. However, the mechanism determining why and how those cells are attracted to the injury site for tendon healing is not understood. Since the tenocytes near the injury site go through apoptosis or necrosis following injury, we hypothesized that secretions from injured tenocytes might have biological effects on cell proliferation and migration to enhance tendon healing. Tenocyte apoptosis was induced by 24 h cell starvation. Apoptotic body-rich media (T-ABRM) and apoptotic body-depleted media (T-ABDM) were collected from culture media after centrifuging. Tenocytes and bone marrow-derived stem cells (BMDSCs) were isolated and cultured with the following four media: (1) T-ABRM, (2) T-ABDM, (3) GDF-5, or (4) basal medium with 2% fetal calf serum (FCS). The cell activities and functions were evaluated. Both T-ABRM and T-ABDM treatments significantly stimulated the cell proliferation, migration, and extracellular matrix synthesis for both tenocytes and BMDSCs compared to the control groups (GDF-5 and basal medium). However, cell proliferation, migration, and extracellular matrix production of T-ABRM-treated cells were significantly higher than the T-ABDM, which indicates the apoptotic bodies are critical for cell activities. Our study revealed the possible mechanism of the intrinsic healing of the tendon in which apoptotic bodies, in the process of apoptosis, following tendon injury promote tenocyte and stromal cell proliferation, migration, and production. Future studies should analyze the components of the apoptotic bodies that play this role, and, thus, the targeting of therapeutics can be developed. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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20 pages, 3044 KiB

Open AccessArticle

The Effect of Age and Intrinsic Aerobic Exercise Capacity on the Expression of Inflammation and Remodeling Markers in Rat Achilles Tendons

by Runa Kinitz, Estelle Heyne, Lauren G. Koch, Steven L. Britton, Manuela Thierbach and Britt Wildemann

Int. J. Mol. Sci. 2022, 23(1), 79; https://doi.org/10.3390/ijms23010079 - 22 Dec 2021

Cited by 6 | Viewed by 3896

Abstract

Old age, adiposity, and metabolic disorders are known as risk factors for chronic tendinopathy, which is a common problem in both athletes and the general population. However, the importance of these influencing factors has not yet been well understood. This study investigated alterations in gene expression and histology of Achilles tendons of young (10 weeks) and old (100 weeks) rats bred for low (low capacity runners, LCR) and high (high capacity runners, HCR) intrinsic aerobic exercise capacity. In this rat model, LCR displayed a phenotype of reduced exercise capacity, higher body weight, and metabolic dysfunctions compared to HCR. We hypothesized that the risk factors for tendinopathy in old LCR could lead to more pronounced impairments in Achilles tendon tissue. In quantitative real-time PCR (qPCR), age-related downregulation of tenocyte markers e.g., tenomodulin, genes related to matrix modeling and remodeling (e.g., collagens, elastin, biglycan, fibronectin, tenascin C) as well as transforming growth factor beta 3 (Tgfb3) have been detected. Inflammation marker cyclooxygenase 2 (Cox2) was downregulated in old rats, while microsomal prostaglandin E synthase 2 (Ptges2) was upregulated in old HCR and old LCR. In all groups, interleukin 6 (Il6), interleukin 1 beta (Il1b), and tumor necrosis factor alpha (Tnfa) showed no significant alteration. In histological evaluation, tendons of old rats had fewer and more elongated tenocyte nuclei than young rats. Even though a higher content of glycosaminoglycans, a sign of degeneration, was found in old HCR and LCR, no further signs of tendinopathy were detectable in tendons of old rats by histological evaluation. Low intrinsic aerobic exercise capacity and the associated phenotype did not show significant effects on gene expression and tendon histology. These findings indicate that aging seems to play a prominent role in molecular and structural alterations of Achilles tendon tissue and suggests that other risk factors associated with intrinsic aerobic exercise capacity are less influential in this rat model. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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Review

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15 pages, 4179 KiB

Open AccessReview

Anterior Cruciate Ligament Reconstruction: Is Biological Augmentation Beneficial?

by Emerito Carlos Rodríguez-Merchán

Int. J. Mol. Sci. 2021, 22(22), 12566; https://doi.org/10.3390/ijms222212566 - 22 Nov 2021

Cited by 12 | Viewed by 9225

Abstract

Surgical reconstruction in anterior cruciate ligament (ACL) ruptures has proven to be a highly effective technique that usually provides satisfactory results. However, despite the majority of patients recovering their function after this procedure, ACL reconstruction (ACLR) is still imperfect. To improve these results, various biological augmentation (BA) techniques have been employed mostly in animal models. They include: (1) growth factors (bone morphogenetic protein, epidermal growth factor, granulocyte colony-stimulating factor, basic fibroblast growth factor, transforming growth factor-β, hepatocyte growth factor, vascular endothelial growth factor, and platelet concentrates such as platelet-rich plasma, fibrin clot, and autologous conditioned serum), (2) mesenchymal stem cells, (3) autologous tissue, (4) various pharmaceuticals (matrix metalloproteinase-inhibitor alpha-2-macroglobulin bisphosphonates), (5) biophysical/environmental methods (hyperbaric oxygen, low-intensity pulsed ultrasound, extracorporeal shockwave therapy), (6) biomaterials (fixation methods, biological coatings, biosynthetic bone substitutes, osteoconductive materials), and (7) gene therapy. All of them have shown good results in experimental studies; however, the clinical studies on BA published so far are highly heterogeneous and have a low degree of evidence. The most widely used technique to date is platelet-rich plasma. My position is that orthopedic surgeons must be very cautious when considering using PRP or other BA methods in ACLR. Full article

(This article belongs to the Special Issue Research Progress on Molecular Repair of Tendon/Ligament)

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