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Tendon Homeostasis in Hypercholesterolemia

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Metabolic Influences on Risk for Tendon Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 920))

Abstract

Hypercholesterolemia is a serious health problem that is associated not only with heart disease, but also tendon pathology. In high cholesterol environments (e.g. familial hyperlipidemia), lipids accumulate within the tendon extracellular matrix and form deposits called xanthomas. Lipid-related changes are known to affect several tendon mechanical properties, including stiffness and modulus, in uninjured and injured tendons, alike. Mechanisms to explain these cholesterol-related changes are multiple, including alterations in tenocyte gene and protein expression, matrix turnover, tissue vascularity, and cytokine production. Clinically, rotator cuff tear and Achilles tendon rupture are clearly associated with metabolic derangements, and elevated total cholesterol is often among the specific metabolic parameters implicated. Treatment of hypercholesterolemia using statin medications has also been shown to affect tendon properties, resulting in normalization of tendon thickness and improved tendon healing. Despite current work, the pathophysiology of lipid-related tendon pathology remains incompletely understood, and additional hypothesis-generating studies, including those incorporating whole-genome and whole-transcriptome technologies, will help to point the field in new directions.

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Abbreviations

A-20:

low-dose atorvastatin

A-80:

high-dose atorvastatin

ApoE:

apolipoprotein E

ATV:

atorvastatin

BMI:

body mass index

BMP-2:

bone morphogenetic protein 2

CEL:

celecoxib

COX2:

cyclooxygenase 2

CSA:

cross-sectional area

CXCL3:

chemokine (C-X-C motif) ligand 3

FH:

familial hyperlipidemia

GTPase:

hydrolase enzyme that binds and hydrolyzes guanosine triphosphate (GTP)

HC:

high cholesterol

HDL:

high-density lipoprotein

IL-6,-8:

interleukin-6,-8

LDL:

low-density lipoprotein

MMP:

matrix metalloproteinase

PGE2:

prostaglandin E2

Rap1a:

Ras-related protein Rap-1A

RC:

rotator cuff

S-20:

low-dose simvastatin

S-80:

high-dose simvastatin

TNF-alpha:

tumor necrosis factor alpha

TX-:

patients without tendon xanthomas

TX+:

patients with tendon xanthomas

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Author information

Authors and Affiliations

  1. McKay Orthopaedic Laboratory, University of Pennsylvania, Philadelphia, PA, USA

    Louis J. Soslowsky & George W. Fryhofer

Authors
  1. Louis J. Soslowsky
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  2. George W. Fryhofer
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Corresponding author

Correspondence to Louis J. Soslowsky .

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Editors and Affiliations

  1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Paul W. Ackermann

  2. McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada

    David A. Hart

Glossary

Apolipoprotein E (ApoE)

a class of lipoprotein important for normal catabolism of triglyceride-rich lipoprotein components; some genetic variants are associated with high levels of circulating cholesterol.

Celecoxib

an anti-inflammatory drug that blocks transformation of arachidonic acid to prostaglandin precursors via reversible inhibition of the cyclooxygenase-2 (COX-2) enzyme.

Familial hyperlipidemia

a heritable medical condition characterized by abnormally high levels of lipid or lipoprotein in the blood; often caused by mutation of a lipoprotein receptor or lipoprotein lipase, which prevents normal clearance of lipid and lipoprotein from the blood.

Elastic modulus

a material property that, like stiffness, describes a substance’s ability to resist deformation; however, unlike stiffness, modulus also takes into account cross-sectional area and is defined as the slope of the stress-strain curve in the elastic deformation region for a given substance. Modulus is measured in units of pascals (Pa).

Glycosaminoglycans

negatively charged, linear carbohydrate chains composed of repeating disaccharides; glycosaminoglycans are an important component of tendon extracellular matrix that serve to occupy space and resist compressive forces.

Hypercholesterolemia

medical condition defined as a total serum cholesterol concentration ≥ 240 mg/dL.

Lipoproteins

carrier proteins that bind cholesterol and allow for transport throughout the body

MMP-2, MMP-9

matrix metalloproteinases involved in normal breakdown of the extracellular matrix, including type IV collagen (a main structural component of basement membranes).

Statin

a class of cholesterol-lowering drugs that function through competitive inhibition of the enzyme HMG-CoA reductase, which effectively blocks cholesterol synthesis in the liver and leads to a reduction in circulating cholesterol levels.

Stiffness

the degree to which a substance resists deformation. Stiffness is measured in units of Newtons per meter (N/m).

Xanthoma

on histological examination, a collection of lipid-laden macrophages (foam cells) in the tendon extracellular matrix; xanthomas may also be appreciated on gross examination as subcutaneous nodules tracking along a tendon.

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Soslowsky, L.J., Fryhofer, G.W. (2016). Tendon Homeostasis in Hypercholesterolemia. In: Ackermann, P., Hart, D. (eds) Metabolic Influences on Risk for Tendon Disorders. Advances in Experimental Medicine and Biology, vol 920. Springer, Cham. https://doi.org/10.1007/978-3-319-33943-6_14

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