Editing Tendon (section)

==Clinical significance==

===Injury===
{{anchor|tendon injury}}
Tendons are subject to many types of injuries. There are various forms of [[tendinopathy|tendinopathies]] or tendon injuries due to overuse. These types of injuries generally result in inflammation and degeneration or weakening of the tendons, which may eventually lead to [[tendon rupture]].<ref name = "Sharma P. M">{{cite journal | vauthors = Sharma P, Maffulli N | title = Biology of tendon injury: healing, modeling and remodeling | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 6 | issue = 2 | pages = 181–190 | year = 2006 | pmid = 16849830 | url = https://www.ismni.org/jmni/pdf/24/14MAFFULLI.pdf | url-status = live | archive-url = https://web.archive.org/web/20240105034830/https://www.ismni.org/jmni/pdf/24/14MAFFULLI.pdf | archive-date = Jan 5, 2024 }}</ref> Tendinopathies can be caused by a number of factors relating to the tendon extracellular matrix (ECM), and their classification has been difficult because their symptoms and histopathology often are similar.

Types of tendinopathy include:<ref name="Maffulli 2003">{{cite journal | vauthors = Maffulli N, Wong J, Almekinders LC | title = Types and epidemiology of tendinopathy | journal = Clinics in Sports Medicine | volume = 22 | issue = 4 | pages = 675–692 | date = October 2003 | pmid = 14560540 | doi = 10.1016/s0278-5919(03)00004-8 }}</ref>
* [[Tendinosis]]: non-inflammatory injury to the tendon at the cellular level. The degradation is caused by damage to collagen, cells, and the vascular components of the tendon, and is known to lead to rupture.<ref>{{cite journal | vauthors = Aström M, Rausing A | title = Chronic Achilles tendinopathy. A survey of surgical and histopathologic findings | journal = Clinical Orthopaedics and Related Research | volume = 316 | issue = 316 | pages = 151–164 | date = July 1995 | pmid = 7634699 | doi = 10.1097/00003086-199507000-00021 | s2cid = 25486134 }}</ref> Observations of tendons that have undergone spontaneous rupture have shown the presence of collagen fibrils that are not in the correct parallel orientation or are not uniform in length or diameter, along with rounded tenocytes, other cell abnormalities, and the ingrowth of blood vessels.<ref name="Sharma P. M"/> Other forms of tendinosis that have not led to rupture have also shown the degeneration, disorientation, and thinning of the collagen fibrils, along with an increase in the amount of glycosaminoglycans between the fibrils.<ref name="Sharma, P. 2005">{{cite journal | vauthors = Sharma P, Maffulli N | title = Tendon injury and tendinopathy: healing and repair | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 87 | issue = 1 | pages = 187–202 | date = January 2005 | pmid = 15634833 | doi = 10.2106/JBJS.D.01850 | s2cid = 1111422 }}</ref>
* [[Tendinitis]]: degeneration with inflammation of the tendon as well as vascular disruption.<ref name="Jozsa, L. 1997"/>
* [[Paratenonitis]]: inflammation of the paratenon, or paratendinous sheet located between the tendon and its sheath.<ref name="Maffulli 2003"/>

Tendinopathies may be caused by several intrinsic factors including age, body weight, and nutrition. The extrinsic factors are often related to sports and include excessive forces or loading, poor training techniques, and environmental conditions.<ref name="Riley, G. 2004">{{cite journal | vauthors = Riley G | title = The pathogenesis of tendinopathy. A molecular perspective | journal = Rheumatology | volume = 43 | issue = 2 | pages = 131–142 | date = February 2004 | pmid = 12867575 | doi = 10.1093/rheumatology/keg448 | doi-access = free }}</ref>

===Healing===
It was believed that tendons could not undergo matrix turnover and that tenocytes were not capable of repair. However, it has since been shown that, throughout the lifetime of a person, tenocytes in the tendon actively synthesize matrix components as well as enzymes such as [[matrix metalloproteinases]] (MMPs) can degrade the matrix.<ref name="Riley, G. 2004"/> Tendons are capable of healing and recovering from injuries in a process that is controlled by the tenocytes and their surrounding extracellular matrix.

The three main stages of tendon healing are inflammation, repair or proliferation, and remodeling, which can be further divided into consolidation and maturation. These stages can overlap with each other. In the first stage, inflammatory cells such as [[neutrophils]] are recruited to the injury site, along with [[erythrocytes]]. [[Monocytes]] and [[macrophages]] are recruited within the first 24 hours, and [[phagocytosis]] of [[necrotic]] materials at the injury site occurs. After the release of [[vasoactive]] and [[chemotactic]] factors, [[angiogenesis]] and the [[cell growth|proliferation]] of tenocytes are initiated. Tenocytes then move into the site and start to synthesize collagen III.<ref name="Sharma P. M"/><ref name="Sharma, P. 2005"/> After a few days, the repair or proliferation stage begins. In this stage, the tenocytes are involved in the synthesis of large amounts of collagen and proteoglycans at the site of injury, and the levels of GAG and water are high.<ref name="Wang, J. H. C. 2006">{{cite journal | vauthors = Wang JH | title = Mechanobiology of tendon | journal = Journal of Biomechanics | volume = 39 | issue = 9 | pages = 1563–1582 | year = 2006 | pmid = 16000201 | doi = 10.1016/j.jbiomech.2005.05.011 }}</ref> After about six weeks, the remodeling stage begins. The first part of this stage is consolidation, which lasts from about six to ten weeks after the injury. During this time, the synthesis of collagen and GAGs is decreased, and the cellularity is also decreased as the tissue becomes more fibrous as a result of increased production of collagen I and the fibrils become aligned in the direction of mechanical stress.<ref name="Sharma, P. 2005"/> The final maturation stage occurs after ten weeks, and during this time there is an increase in crosslinking of the collagen fibrils, which causes the tissue to become stiffer. Gradually, over about one year, the tissue will turn from fibrous to scar-like.<ref name="Wang, J. H. C. 2006"/>

Matrix metalloproteinases (MMPs) have a very important role in the degradation and remodeling of the ECM during the healing process after a tendon injury. Certain MMPs including MMP-1, MMP-2, MMP-8, MMP-13, and MMP-14 have collagenase activity, meaning that, unlike many other enzymes, they are capable of degrading collagen I fibrils. The degradation of the collagen fibrils by MMP-1 along with the presence of denatured collagen are factors that are believed to cause weakening of the tendon ECM and an increase in the potential for another rupture to occur.<ref>{{cite journal | vauthors = Riley GP, Curry V, DeGroot J, van El B, Verzijl N, Hazleman BL, Bank RA | title = Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology | journal = Matrix Biology | volume = 21 | issue = 2 | pages = 185–195 | date = March 2002 | pmid = 11852234 | doi = 10.1016/S0945-053X(01)00196-2 }}</ref> In response to repeated mechanical loading or injury, [[cytokines]] may be released by tenocytes and can induce the release of MMPs, causing degradation of the ECM and leading to recurring injury and chronic tendinopathies.<ref name="Sharma, P. 2005"/>

A variety of other molecules are involved in tendon repair and regeneration. There are five growth factors that have been shown to be significantly upregulated and active during tendon healing: [[insulin-like growth factor 1]] (IGF-I), [[platelet-derived growth factor]] (PDGF), [[vascular endothelial growth factor]] (VEGF), [[basic fibroblast growth factor]] (bFGF), and [[transforming growth factor beta]] (TGF-β).<ref name="Wang, J. H. C. 2006"/> These growth factors all have different roles during the healing process. IGF-1 increases collagen and proteoglycan production during the first stage of inflammation, and PDGF is also present during the early stages after injury and promotes the synthesis of other growth factors along with the synthesis of DNA and the proliferation of tendon cells.<ref name="Wang, J. H. C. 2006"/> The three isoforms of TGF-β (TGF-β1, TGF-β2, TGF-β3) are known to play a role in wound healing and scar formation.<ref>{{cite journal | vauthors = Moulin V, Tam BY, Castilloux G, Auger FA, O'Connor-McCourt MD, Philip A, Germain L | title = Fetal and adult human skin fibroblasts display intrinsic differences in contractile capacity | journal = Journal of Cellular Physiology | volume = 188 | issue = 2 | pages = 211–222 | date = August 2001 | pmid = 11424088 | doi = 10.1002/jcp.1110 | s2cid = 22026692 }}</ref> VEGF is well known to promote angiogenesis and to induce endothelial cell proliferation and migration, and VEGF mRNA has been shown to be expressed at the site of tendon injuries along with collagen I mRNA.<ref>{{cite journal | vauthors = Boyer MI, Watson JT, Lou J, Manske PR, Gelberman RH, Cai SR | title = Quantitative variation in vascular endothelial growth factor mRNA expression during early flexor tendon healing: an investigation in a canine model | journal = Journal of Orthopaedic Research | volume = 19 | issue = 5 | pages = 869–872 | date = September 2001 | pmid = 11562135 | doi = 10.1016/S0736-0266(01)00017-1 | s2cid = 20903366 | doi-access = free }}</ref> Bone morphogenetic proteins (BMPs) are a subgroup of TGF-β superfamily that can induce bone and cartilage formation as well as tissue differentiation, and BMP-12 specifically has been shown to influence formation and differentiation of tendon tissue and to promote fibrogenesis.

====Effects of activity on healing====
In animal models, extensive studies have been conducted to investigate the effects of mechanical strain in the form of activity level on tendon injury and healing. While stretching can disrupt healing during the initial inflammatory phase, it has been shown that controlled movement of the tendons after about one week following an acute injury can help to promote the synthesis of collagen by the tenocytes, leading to increased tensile strength and diameter of the healed tendons and fewer adhesions than tendons that are immobilized. In chronic tendon injuries, mechanical loading has also been shown to stimulate fibroblast proliferation and collagen synthesis along with collagen realignment, all of which promote repair and remodeling.<ref name="Wang, J. H. C. 2006"/> To further support the theory that movement and activity assist in tendon healing, it has been shown that immobilization of the tendons after injury often has a negative effect on healing. In rabbits, collagen fascicles that are immobilized have shown decreased tensile strength, and immobilization also results in lower amounts of water, proteoglycans, and collagen crosslinks in the tendons.<ref name="Sharma P. M"/>

Several [[mechanotransduction]] mechanisms have been proposed as reasons for the response of tenocytes to mechanical force that enable them to alter their gene expression, protein synthesis, and cell phenotype, and eventually cause changes in tendon structure. A major factor is mechanical deformation of the [[extracellular matrix]], which can affect the [[actin cytoskeleton]] and therefore affect cell shape, motility, and function. Mechanical forces can be transmitted by focal adhesion sites, [[integrins]], and cell-cell junctions. Changes in the actin cytoskeleton can activate integrins, which mediate "outside-in" and "inside-out" signaling between the cell and the matrix. [[G-proteins]], which induce intracellular signaling cascades, may also be important, and ion channels are activated by stretching to allow ions such as calcium, sodium, or potassium to enter the cell.<ref name="Wang, J. H. C. 2006"/>