Cyclical strain modulates metalloprotease and matrix gene expression in human tenocytes via activation of TGFβ

Jones, Eldon M.; Jones, Gavin C.; Legerlotz, Kirsten; Riley, Graham P.

doi:10.1016/j.bbamcr.2013.06.019

Cited by 57 publications

(50 citation statements)

References 97 publications

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“…A less active metabolic response from the tenocytes from tendinopathic tendon was also observed by Jones et al, when these same cell populations were subject to 5% cyclic strain at 1 Hz in collagen gels using a flexcell system. Both of these studies adopted 3D models, and it is unclear how this may relate to the 2D response.…”

Section: Discussionsupporting

confidence: 65%

“…However, previous studies have demonstrated that housing cells in a 3D environment can provide a more physiologically relevant cell environment as a basis for such investigations . For example, using 3D collagen gels, human Achilles tenocytes have been reported to express increases in ADAMTS2/4/16, MMP24, TIMP3, and type I collagen gene expression after 24‐ or 48‐hours loading …”

Section: Introductionmentioning

confidence: 99%

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An in vitro investigation into the effects of 10 Hz cyclic loading on tenocyte metabolism

Udeze

Jones

Riley

et al. 2019

Scandinavian Med Sci Sports

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Tendinopathy is a prevalent, highly debilitating condition, with poorly defined etiology. A wide range of clinical treatments has been proposed, with systematic reviews largely supporting shock wave therapy or eccentric exercise. Characterizing these treatments have demonstrated both generate perturbations within tendon at a frequency of approximately 8‐12 Hz. Consequently, it is hypothesized that loading in this frequency range initiates increased anabolic tenocyte behavior, promoting tendon repair. The primary aim of this study was to investigate the effects of 10 Hz perturbations on tenocyte metabolism, comparing gene expression in response to a 10 Hz and 1 Hz loading profile. Tenocytes from healthy and tendinopathic human tendons were seeded into 3D collagen gels and subjected to 15 minutes cyclic strain at 10 Hz or 1 Hz. Tenocytes from healthy tendon showed increased expression of all analyzed genes in response to loading, with significantly increased expression of inflammatory and degradative genes with 10 Hz, relative to 1 Hz loading. By contrast, whilst the response of tenocytes from tendinopathy tendon also increased with 10 Hz loading, the overall response profile was more varied and less intense, possibly indicative of an altered healing response. Through inhibition of the pathway, IL1 was shown to be involved in the degradative and catabolic response of cells to high‐frequency loading, abrogating the loading response. This study has demonstrated for the first time that loading at a frequency of 10 Hz may enhance the metabolic response of tenocytes by initiating an immediate degradatory and inflammatory cell response through the IL1 pathway, perhaps as an initial stage of tendon healing.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

An in vitro investigation into the effects of 10 Hz cyclic loading on tenocyte metabolism

Udeze

Jones

Riley

et al. 2019

Scandinavian Med Sci Sports

Self Cite

View full text Add to dashboard Cite

show abstract

“…3D loading is superior to 2D loading as a result of its greater resemblance to native tissue. Current 3D loading platforms used in tendon mechanobiology are mostly based on collagen gel scaffolds; however, the integration between cells and the collagen gel is different from tenocytes with collagen fibers (31)(32)(33)(34). In our study, we generated 3D TDSC constructs by stimulating TDSCs to generate ECM, which closely mimics the binding between cells and the ECM in tendon tissue.…”

Section: Discussionmentioning

confidence: 99%

3D uniaxial mechanical stimulation induces tenogenic differentiation of tendon‐derived stem cells through a PI3K/AKT signaling pathway

et al. 2018

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The tendon is a mechanosensitive tissue, but little is known about how mechanical stimulation selectively signals tenogenic differentiation and neo-tendon formation. In this study, we compared the impact of uniaxial and biaxial mechanical loading on tendon-derived stem cells (TDSCs). Our data show that there are variations in cell signaling and cell differentiation of mouse TDSCs in response to uniaxial and biaxial loading in monolayer culture. Whereas uniaxial loading induced TDSCs toward tenogenic and osteogenic differentiation, biaxial loading induced osteogenic, adipogenic, and chondrogenic differentiation of TDSCs. Furthermore, by applying uniaxial loading on 3-dimensional (3D) TDSC constructs, tenogenic-specific differentiation and neo-tendon formation were observed, results that were replicated in human TDSCs. We also showed that uniaxial loading induced PKB (AKT) phosphorylation (pAKT), whereas biaxial loading induced pERK. Most importantly, we found that inhibition of the PI3K/AKT signaling pathway could attenuate tenogenic differentiation and tendon formation in 3D TDSC constructs subjected to uniaxial loading. Taken together, our study highlights the importance of appropriate mechanobiological stimulation in 3D cell niches on tendon-like tissue formation and demonstrates that uniaxial mechanical loading plays an essential role in tenogenic differentiation and tendon formation by activating the PI3K/AKT signaling pathway.-Wang, T., Thien, C., Wang, C., Ni, M., Gao, J., Wang, A., Jiang, Q., Tuan, R. S., Zheng, Q., Zheng, M. H. 3D uniaxial mechanical stimulation induces tenogenic differentiation of tendon-derived stem cells through a PI3K/AKT signaling pathway.

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“…In pathological conditions, static compression stress activates excess TGFβ1819. In the physiologic state, TGFβ maintains chondrocyte homeostasis to preserve EP structure and function202122.…”

Section: Discussionmentioning

confidence: 99%

Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis

Bian

Jain

et al. 2016

Sci Rep

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Narrowed intervertebral disc (IVD) space is a characteristic of IVD degeneration. EP sclerosis is associated with IVD, however the pathogenesis of EP hypertrophy is poorly understood. Here, we employed two spine instability mouse models to investigate temporal and spatial EP changes associated with IVD volume, considering them as a functional unit. We found that aberrant mechanical loading leads to accelerated ossification and hypertrophy of EP, decreased IVD volume and increased activation of TGFβ. Overexpression of active TGFβ in CED mice showed a similar phenotype of spine instability model. Administration of TGFβ Receptor I inhibitor attenuates pathologic changes of EP and prevents IVD narrowing. The aberrant activation of TGFβ resulting in EPs hypertrophy-induced IVD space narrowing provides a pharmacologic target that could have therapeutic potential to delay DDD.Degenerative disc disease (DDD) is one of the most common musculoskeletal disorders that is associated with disability and absenteeism from work. Degeneration has been detected as early as teenage years and severe degeneration is found in 60% of 70-year olds 1,2 . DDD typically presents with back pain and imposes an enormous socio-economic burden, over $100 billion annually in the US alone. This cost exceeds the combined costs of stroke, respiratory infection, diabetes, coronary artery disease and rheumatoid disease 1,2 . Several factors have been implicated to cause DDD such as aging, genetic predisposition, toxic factors, metabolic disorders, low-grade infection, neurogenic inflammation and mechanical factors 3 . However, the pathogenesis of DDD under mechanical loading environment is not well known.Intervertebral disc (IVD) is composed of three parts: gel-like nucleus pulposus (NP) in the central compartment surrounded by an annulus fibrosis (AF) ring, and both cranial and caudal cartilage endplates (EPs) that attach the IVD inner ring to the adjacent vertebrae. EPs transmit mechanical loads produced by body weight and muscle activity between the bony vertebrae and soft tissue 4 . Moreover, EPs serve as a selective permeability barrier, allowing passage of small solutes, such as nutrient substances but impeding transport of larger solutes such as inflammatory factors 5 . Sclerosis of EPs change the mechanical property and impair diffusion and nutrient supply, thus accelerating IVD degeneration 5 . However, the originating mechanism of EP pathology is still not clearly understood.EPs undergo calcification and ossification and become sclerotic with aging 6 . We have previously found that excess activation of TGFβ causes sclerosis and angiogenesis of subchondral bone in the knee joint, which alters loading distribution on articular cartilage and is key in the pathogenesis of osteoarthritis (OA) 7,8 . Upregulation of TGFβ has been observed in calcified hypertrophic EPs of degenerative IVD 9 . Whether TGFβ is involved in EP sclerotic changes is unknown.In this study, we investigated temporal and spatial EP changes resulting from mechanical stress by...

show abstract

Cyclical strain modulates metalloprotease and matrix gene expression in human tenocytes via activation of TGFβ

Cited by 57 publications

References 97 publications

An in vitro investigation into the effects of 10 Hz cyclic loading on tenocyte metabolism

An in vitro investigation into the effects of 10 Hz cyclic loading on tenocyte metabolism

3D uniaxial mechanical stimulation induces tenogenic differentiation of tendon‐derived stem cells through a PI3K/AKT signaling pathway

Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis

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