Tendinopathy and tears of the rotator cuff are associated with hypoxia and apoptosis

Benson, Richard T.; McDonnell, Susan; Knowles, Helen J.; Rees, Jonathan; Carr, Andrew; Hulley, P A

doi:10.1302/0301-620x.92b3.23074

Cited by 128 publications

(124 citation statements)

References 36 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the promoter assay results demonstrated that HIF1‐mediated Fabp4 gene regulation depends on the HIF1 response element in the Fabp4 promoter. A previous study demonstrated that tendinopathy and RCT are associated with hypoxia and apoptosis 39. It has been also reported that tendon retraction in full‐thickness medium‐sized RCT is characterized by neovascularity, increased VEGF/HIF expression, fatty infiltration, and muscle atrophy,40 showing substantial involvement of HIF1 in RCT.…”

Section: Discussionmentioning

confidence: 95%

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Lee

Kim

et al. 2017

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

BackgroundFatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid‐binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model.MethodsIn the RCT model, we evaluated the expression of FABP4 by qRT‐PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia‐inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively.ResultsFABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear‐induced FABP4 expression was up‐regulated by hypoxia. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1β. Hypoxia‐induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment.ConclusionsThis study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.

show abstract

Section: Discussionmentioning

confidence: 95%

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Lee

Kim

et al. 2017

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

show abstract

“…These studies may provide support for the use of MSCs in the treatment of equine tendonitis. Tendon injuries are characterized by hypoxic degeneration which leads to tenocyte apoptosis, particularly in chronic injury [17,18]. …”

Section: Msc Activation and Preconditioningmentioning

confidence: 99%

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

Borjesson

Peroni

2011

Clinics in Laboratory Medicine

View full text Add to dashboard Cite

“…Therefore, hypoxia could regulate apoptosis by increasing its rate, especially in severe tendinopathy. The detection of increased hypoxic markers in the early stages of tendinopathy proved that hypoxia is involved in the regulation of apoptosis, probably as a consequence of the release of factors involved in reparative and degenerative pathways of the tendon [2]. Therefore, in hypoxic conditions, a dynamic balance between proapoptotic and anti-apoptotic mediators is crucial in the healing process [17].…”

Section: Resultsmentioning

confidence: 99%

“…Emerging concepts highlight that cuff tendinopathy, and eventually tendon tears, could be the result of an abnormal inflammatory status and unbalanced enzymatic cascades within the tissue involved [1,4]. Extrinsic causes such as repetitive microtrauma in overhead athletes and subacromial impingement in older individuals also play a role in the pathogenesis of this multifactorial condition [2,16], due to the altered cellular metabolism in association with aging processes (degeneration [1], abnormal apoptosis [2], and chronic inflammation [8]). Based on the concept of 'critical area' of the supraspinatus described by Codman, hypovascularization may predispose to the development of tendinopathy [3].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endothelial dysfunction and tendinopathy: how far have we come?

et al. 2013

View full text Add to dashboard Cite

Symptomatic tendon tears are one of the most important causes of pain and joint dysfunction. Among the intrinsic causes, vascularization recently gained a major role. Endothelial function is indeed a key factor, as well as vascular tone and thrombotic factors, in the regulation of vascular homeostasis and the composition of vascular wall. In this review, we studied systematically whether there is a relationship between endothelial dysfunction and tendinopathy. A literature search was performed using the isolated or combined keywords endothelial dysfunction and tendon,' 'nitric oxide (NO) and tendinopathy,' and 'endothelial dysfunction in tendon healing.' We identified 21 published studies. Of the selected studies, 9 were in vivo studies, 2 focusing on animals and 7 on humans, while 12 reported about in vitro evaluations, where 7 were carried out on humans and 5 on animals. The evidence about a direct relationship between tendinopathy and endothelial dysfunction is still poor. As recent studies have shown, there is no significant improvement in clinical and functional assessments after treatment with NO in patients suffering from tendinopathy in different locations. No significant differences were identified in the outcomes reported for experiment group when compared with controls treated with conventional surgical procedures or rehabilitation programs. Nitric oxide could be a marker to quantify the response of the endothelium to mechanical stress or hypoxia indicating the final balance between vasodilatating and vasoconstricting factors and their effects, but more ad stronger evidence is still needed to fully support this practice.

show abstract

Tendinopathy and tears of the rotator cuff are associated with hypoxia and apoptosis

Cited by 128 publications

References 36 publications

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

Endothelial dysfunction and tendinopathy: how far have we come?

Contact Info

Product

Resources

About