Review

Authors: Stavros Thomopoulos, William C Parks, Daniel B Rifkin...

Tendon disorders are common and lead to significant disability, pain, healthcare cost, and lost productivity. A wide range of injury mechanisms exist leading to tendinopathy or tendon rupture. Tears can occur in healthy tendons that are acutely overloaded (e.g., during a high speed or high impact event) or lacerated (e.g., a knife injury). Tendinitis or tendinosis can occur in tendons exposed to overuse conditions (e.g., an elite swimmer's training regimen) or intrinsic tissue degeneration (e.g., age-related degeneration). The healing potential of a torn or pathologic tendon varies depending on anatomic location (e.g., Achilles vs. rotator cuff) and local environment (e.g., intrasynovial vs. extrasynovial). Although healing occurs to varying degrees, in general healing of repaired tendons follows the typical wound healing course, including an early inflammatory phase, followed by proliferative and remodeling phases. Numerous treatment approaches have been attempted to improve tendon healing, including growth factor- and cell-based therapies and rehabilitation protocols. This review will describe the current state of knowledge of injury and repair of the three most common tendinopathies--flexor tendon lacerations, Achilles tendon rupture, and rotator cuff disorders--with a particular focus on the use of animal models for understanding tendon healing.

Topics: Animals; Humans; Models, Animal; Tendon Injuries; Wound Healing

PubMed: 25641114
DOI: 10.1002/jor.22806

Review

Authors: Faezeh Samadi, Mohammad Saeed Kahrizi, Fateme Heydari...

BACKGROUND

Osteoarthritis (OA), as one of the chronic debilitating conditions, affects 15% of people globally and is linked with serious problems, such as cardiovascular diseases, metabolic syndrome, and autoimmune inflammatory disorders. The current therapeutic options for this disease include nonsteroidal anti-inflammatory drugs, surgery, gene therapy, intrasynovial gel injection, and warm needle penetration. However, these approaches may be accompanied by considerable side effects, high costs, and some limitations for patients. Thus, using an alternative way is needed.

SUMMARY

Presently, natural compounds based-therapies, like flavonoids, have acquired much attention in the current era. One of the compounds belonging to the flavonoid family is quercetin, and its therapeutic effects on disorders related to joints and cartilage have been addressed in vivo and in vitro studies.

KEY MESSAGES

In this review, we summarized evidence indicating its curative capacity against OA with a mechanistic insight.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Osteoarthritis; Quercetin

PubMed: 35793647
DOI: 10.1159/000525494

Review

Authors: Douglas M Sammer, Kevin C Chung

The intrasynovial flexor tendons of the hand are critical for normal hand function. Injury to these tendons can result in absent finger flexion, and a subsequent loss of overall hand function. The surgical techniques used to repair these tendons have improved in the past few decades, as have the postoperative rehabilitation protocols. In spite of these advances, intrasynovial flexor tendon repairs continue to be plagued by postoperative scar formation, which limits tendon gliding and prevents a full functional recovery. This paper describes the current challenges of flexor tendon repair, and evaluates the most recent advances and strategies for achieving an excellent functional outcome.

Topics: Biomechanical Phenomena; Cicatrix; Hand Injuries; Humans; Postoperative Care; Recovery of Function; Suture Techniques; Tendon Injuries; Tendons; Wound Healing

PubMed: 24813361
DOI: 10.1111/wrr.12161

Review

Authors: Benjamin B Rothrauff, Rocky S Tuan

The intrasynovial bone-tendon interface is a gradual transition from soft tissue to bone, with two intervening zones of uncalcified and calcified fibrocartilage. Following injury, the native anatomy is not restored, resulting in inferior mechanical properties and an increased risk of re-injury. Recent in vivo studies provide evidence of improved healing when surgical repair of the bone-tendon interface is augmented with cells capable of undergoing chondrogenesis. In particular, cellular therapy in bone-tendon healing can promote fibrocartilage formation and associated improvements in mechanical properties. Despite these promising results in animal models, cellular therapy in human patients remains largely unexplored. This review highlights the development and structure-function relationship of normal bone-tendon insertions. The natural healing response to injury is discussed, with subsequent review of recent research on cellular approaches for improved healing. Finally, opportunities for translating in vivo findings into clinical practice are identified.

Topics: Bone Regeneration; Bone and Bones; Cell- and Tissue-Based Therapy; Humans; Osteogenesis; Tendons

PubMed: 24326955
DOI: 10.4161/org.27404

Authors: Richard H Gelberman, Ryan A Lane, Shelly E Sakiyama-Elbert...

Enriched in glycolytic enzymes, paucicellular and hypovascular intrasynovial flexor tendons fail to mount an effective healing response after injury and repair. In contrast, well-vascularized extrasynovial flexor tendons possess high levels of oxidative phosphorylation (OXPHOS) enzymes and have a markedly improved healing capacity. This study was designed to compare the metabolic profiles of the two types of tendons and to evaluate the impact of metabolic reprogramming on early intrasynovial tendon healing in a clinically relevant canine model. Results showed that healthy intrasynovial tendons expressed higher levels of PDK1 and GAPDH and lower levels of SCX and IGF1 than did extrasynovial tendons. PDK1 encodes a subtype of pyruvate dehydrogenase kinase (PDK) that inhibits OXPHOS. Consistently, ATP production via glycolysis was favored in intrasynovial tendon cells whereas OXPHOS was the preferred pathway in extrasynovial tendon cells. Inhibition of glycolysis in vitro increased SCX expression in intrasynovial tendon cells. Therefore, dichloroacetate (DCA), a PDK1 inhibitor, was used in vivo to shift intrasynovial tendon ATP production from glycolysis to OXPHOS. Oral DCA administration reduced serum lactate concentration and increased acetyl-CoA content in repaired intrasynovial tendons and led to reduced TLR4 and IL1B and increased IGF1, SCX, and TGFB3 expressions in treated intrasynovial tendons compared to controls. Immunohistochemistry staining with anti-Ki67 and anti-CD31 antibodies revealed marked increases in cellularity and neovascularization in treated intrasynovial tendons. Clinical significance: The findings of this experiment indicate that improved gene expression and histological outcomes can be achieved by regulating glucose metabolism in the early stages following intrasynovial tendon repair.

Topics: Animals; Dogs; Adenosine Triphosphate; Plastic Surgery Procedures; Tendons

PubMed: 35488732
DOI: 10.1002/jor.25354

Authors: Vivian G Quam, Nadine N Altmann, Matthew T Brokken...

BACKGROUND

Intrasynovial deep digital flexor tendon (DDFT) injuries occur frequently and are often implicated in cases of navicular disease with poor outcomes and reinjuries. Cell-based approaches to tendon healing are gaining traction in veterinary medicine and ultimately may contribute to improved DDFT healing in horses. However, a better understanding of the innate cellular characteristics of equine DDFT is necessary for developing improved therapeutic strategies. Additionally, fibrocartilaginous, intrasynovial tendons like the DDFT are common sites of injury and share a poor prognosis across species, offering translational applications of this research. The objective of this study is to isolate and characterize tendon-derived cells (TDC) from intrasynovial DDFT harvested from within the equine forelimb podotrochlear bursa. TDC from the fibrocartilaginous and tendinous zones are separately isolated and assessed. Flow cytometry is performed for mesenchymal stem cell (MSC) surface markers (CD 29, CD 44, CD 90). Basal tenogenic, osteogenic and chondrogenic markers are assessed via quantitative real time-PCR, and standard trilineage differentiation is performed with third passage TDC from the fibrocartilaginous (fTDC) and tendinous (tTDC) zones of DDFT.

RESULTS

Low-density plating isolated homogenous TDC populations from both zones. During monolayer passage, both TDC subpopulations exhibited clonogenicity, high in vitro proliferation rate, and fibroblast-like morphology. fTDC and tTDC were positive for MSC surface markers CD90 and CD29 and negative for CD44. There were no significant differences in basal tenogenic, osteogenic or chondrogenic marker expression between zones. While fTDC were largely restricted to chondrogenic differentiation, tTDC underwent osteogenic and chondrogenic differentiation. Both TDC subpopulations displayed weak adipogenic differentiation potentials.

CONCLUSIONS

TDC at the level of the podotrochlear bursa, that potentially could be targeted for enhancing DDFT injury healing in horses were identified and characterized. Pending further investigation, promoting chondrogenic properties in cells administered exogenously into the intrasynovial space may be beneficial for intrasynovial tendon regeneration.

Topics: Adipogenesis; Animals; Cell Differentiation; Cells, Cultured; Chondrogenesis; Flow Cytometry; Forelimb; Horses; Mesenchymal Stem Cells; Osteogenesis; Tendons

PubMed: 33794882
DOI: 10.1186/s12917-021-02793-1

Systemic absorption of triamcinolone acetonide is increased from intrasynovial versus extrasynovial sites and induces hyperglycemia, hyperinsulinemia, and suppression of the hypothalamic-pituitary-adrenal axis.

Authors: Kimberly L Hallowell, Katarzyna Dembek, Caitlyn R Horne...

Steroid-associated laminitis remains a major concern with use of corticosteroids in horses. Individual case factors such as joint pathology, pre-existing endocrinopathies, or corticosteroid type, dose, and timing influencing steroid-induced laminitis risk have not been investigated. This study aimed to determine if systemic absorption of triamcinolone acetonide (TA) varies between intrasynovial (antebrachiocarpal) and extrasynovial (sacroiliac) injection sites, and to determine the effects of TA absorption on glucose, insulin, cortisol, and adrenocorticotropic hormone (ACTH). Twenty adult horses were randomized into antebrachiocarpal or sacroiliac joint injection groups, and each horse received bilateral injections with a total dose of 18 mg triamcinolone. Blood was collected prior to injection and at 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, and 72 h post-injection. Peak TA absorption occurred at 8 h in both groups, and was significantly higher in the intrasynovial group compared to the extrasynovial group (1.397 ng/mL, 0.672 ng/mL,  < 0.05). Plasma TA levels were significantly higher in the intrasynovial group from 8 to 36 h post-injection ( < 0.05). There was no difference in glucose, insulin, cortisol, or ACTH between groups at any time point. Insulin and glucose were significantly increased from baseline at all timepoints from 10-72 h and 1-72 h post-injection, respectively. Horses with elevated baseline insulin values (>20 μU/mL) from both groups experienced a more marked hyperinsulinemia, reaching a mean peak insulin of 197.5 μU/mL as compared to 90.06 μU/mL in those with normal baseline insulin. Cortisol and ACTH were significantly decreased from baseline at timepoints from 4-72 h post-injection in both groups. This study is the first to evaluate drug absorption from the sacroiliac site and demonstrates that drug absorption varies between intrasynovial and extrasynovial injection sites. TA absorption causes metabolic derangements, most notably a marked hyperinsulinemia that is more severe in horses with elevated baseline insulin values. The influence of baseline endocrinopathies on response to corticosteroid administration as well as the effect of corticosteroid-induced metabolic derangements warrant further investigation as risk factors for corticosteroid-associated laminitis.

PubMed: 38828366
DOI: 10.3389/fvets.2024.1388470

Authors: Hua Shen, Solaiman Tarafder, Gayoung Park...

Intrasynovial flexor tendon lacerations of the hand are clinically problematic, typically requiring operative repair and extensive rehabilitation. The small-molecule connective tissue growth factor (CTGF) mimics, oxotremorine M (Oxo-M) and 4-PPBP maleate (4-PPBP), have been shown to improve tendon healing in small animal models by stimulating the expansion and differentiation of perivascular CD146+ cells. To enhance intrasynovial flexor tendon healing, small-molecule CTGF mimics were delivered to repaired canine flexor tendons via porous sutures. In vitro studies demonstrated that Oxo-M and 4-PPBP retained their bioactivity and could be released from porous sutures in a sustained manner. However, in vivo delivery of the CTGF mimics did not improve intrasynovial tendon healing. Histologic analyses and expression of tenogenic, extracellular matrix, inflammation, and remodeling genes showed similar outcomes in treated and untreated repairs across two time points. Although in vitro experiments revealed that CTGF mimics stimulated robust responses in extrasynovial tendon cells, there was no response in intrasynovial tendon cells, explaining the lack of in vivo effects. The results of the current study indicate that therapeutic strategies for tendon repair must carefully consider the environment and cellular makeup of the particular tendon for improving the healing response.

Topics: Dogs; Animals; Connective Tissue Growth Factor; Tendons; Sutures; Cell Differentiation

PubMed: 35212415
DOI: 10.1002/jor.25301

Authors: Claire E Welsh, Marco Duz, Timothy D H Parkin...

Electronic medical records from first opinion equine veterinary practice may represent a unique resource for epidemiologic research. The appropriateness of this resource for risk factor analyses was explored as part of an investigation into clinical and pharmacologic risk factors for laminitis. Amalgamated medical records from seven UK practices were subjected to text mining to identify laminitis episodes, systemic or intra-synovial corticosteroid prescription, diseases known to affect laminitis risk and clinical signs or syndromes likely to lead to corticosteroid use. Cox proportional hazard models and Prentice, Williams, Peterson models for repeated events were used to estimate associations with time to first, or subsequent laminitis episodes, respectively. Over seventy percent of horses that were diagnosed with laminitis suffered at least one recurrence. Risk factors for first and subsequent laminitis episodes were found to vary. Corticosteroid use (prednisolone only) was only significantly associated with subsequent, and not initial laminitis episodes. Electronic medical record use for such analyses is plausible and offers important advantages over more traditional data sources. It does, however, pose challenges and limitations that must be taken into account, and requires a conceptual change to disease diagnosis which should be considered carefully.

Topics: Animals; Anti-Inflammatory Agents; Cohort Studies; Electronic Health Records; Foot Diseases; Glucocorticoids; Horse Diseases; Horses; Lameness, Animal; Risk Factors; United Kingdom

PubMed: 28010903
DOI: 10.1016/j.prevetmed.2016.11.012

Authors: Hilda Minerva González-Sánchez, Jea-Hyun Baek, Julia Weinmann-Menke...

Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Carrier Proteins; Inflammation; Interleukins; Mice; Mice, Knockout; Receptor-Like Protein Tyrosine Phosphatases, Class 5; Synovial Membrane

PubMed: 35288653
DOI: 10.1038/s41374-022-00772-0