An overview of structure, mechanical properties, and treatment for age-related tendinopathy

Abstract

Tendons transfer tensile loads from muscle to bone, which enable joint motions and stabilize joints. Tendons sustain large mechanical loads in vivo and as a result, tendons were frequently injured. Aging has been confirmed as a predisposing factor of tendinopathy and bad recovery quality following tendon repair. Current treatment methods are generally not effective and involve either symptomatic relief with non-steroidal antiinflammatory drugs and physical therapy or surgery when conservative treatments failed. The limitation in treatment options is due to our incomplete knowledge of age-related tendinopathy. Studies over the past decades have uncovered a number of important mechanical and cellular changes of aging tendon. However, the basis of aging as a major risk factor for tendon injury and impaired tendon healing remained poorly understood. The objectives of this review are to provide an overview of the current knowledge about the aging-associated changes of structure, mechanical properties and treatment in tendon and highlight causes and therapies for age-related tendinopathy.

Introduction

The average age of the active population is increasing globally with technological advancements in curing life threatening diseases and an awareness to remain active to maintain a healthy life style. It was estimated that by 2030, about 19% of the population in the united States will be over the age of 65 and by 2050 about 19 million people were expected to be 85 years and older accounting to about 4.3% of the population (1). Aging affects multiple aspects of the anatomy and physiology of a person including the tendons, which connect muscles to bones. It lowers the metabolic activity of tendons (2) and tissue regenerative potential. Age-related structural in tendons such as decrease in collagen content may impair tendon healing after injury (3, 4, 5). In addition, aging also reduces the mechanical properties of tendons and predisposes them to re-injury.

The primary function of tendons is to transfer tensile loads from muscle to bone and therefore they are subjected to large mechanical loads in vivo (6, 7, 8). While mechanical loading at physiological levels is beneficial to tendons, excessive loading was detrimental (9). In addition, repetitive high mechanical loading particularly together with cumulative age-related changes in tissue architecture (10) leaded to degenerative changes in tendons and caused various conditions of tendinopathy. Both repetitive motion and high mechanical loading have been shown to increase the levels of the pro-inflammatory mediator, prostaglandin E2 (PGE2), and increase deoxyribonucleic acid and protein synthesis in vitro 1, 11, 12. Cyclical loading also leaded to cumulative damage resulting in diminished matrix repair, which was most likely due to fragmentation of extracellular matrix proteins in vivo (13). In fact aging exaggerated the loss of functional via load-induced proteolytic disruption of the extracellular matrix (ECM) (14).

A newly discovered critical component of tendons called tendon stem cells (TSCs) 3, 15, 16 were also impacted by aging. TSCs are critical for ongoing tissue maintenance and repair and are often postulated to be depleted or dysfunctional in aging tendons 15, 17. Decrease in TSCs number and/or activity creates an imbalance in the maintenance and regeneration of tendons. More important is the reduction in the stemness of TSCs 18, 19, which is critical for generating new tendon tissue after tendon injury. TSCs also play a critical role in the development of tendinopathy in part by undergoing aberrant differentiation into nontenocytes that impart inferior biological characteristics on to tendons (20). Age-related changes within stem cell niches and mechanical loading (21) are another significant factors that contribute to reduced tissue homeostasis and regeneration in older individuals.

In general, current methods to treat tendinopathy are not very effective and involve symptomatic relief. When such conservative treatments fail, often reconstruction surgeries such as those performed for ACL reconstruction are sought. Even these treatments did not completely repair tendons because of their inability to re-establish the biomechanical properties of the normal tendon in the linear range. Most repaired tendons have scar formation and were prone to re-injury because of inferior biomechanical properties. The limitations in the treatment options for tendinopathy were due to our incomplete understanding of the degenerative disorders of tendons particularly related to older ages. Most of our knowledge on tendon physiology and tendinopathy stems from studies on animal models (9, 22, 23, 24) and young and active humans particularly athletes (25, 26, 27).

Optimal tendon function depends both on intrinsic protein synthesizing capacity, circulating stimulating hormonal factors, and extrinsic mechanical loading to maintain the balance between protein synthesis and breakdown (28). Although it is intuitive that quality of aging tendons can be improved by strengthening the synthesizing capacity, applying moderate mechanical loading and exposing to stimulating factors, the extent of recovery in aged-tendons has not been studied thoroughly yet. In this review we present the existing knowledge on the structure and mechanical properties of aging tendons, and analyze the existing treatment options for age-related tendinopathy.

Aging alters tendon structure

Morphological changes of aging tendons

Tendons are dense connective tissues composed of a number of cell types including endothelial cells, synovial cells, chondrocytes, tenoblasts, tenocytes and tendon stem/projenitor cells (TSCs). Normal tendons have a multi-unit hierarchical structure composed of collagen molecules, fibrils, fiber bundles, fascicles and tendon units arrange in the longitudinal axis 6, 29. This organization is altered in aging tendons and is more similar to tendinopathic tendons, which were characterized by increased lipid deposition, ossification and PGE2 accumulation (20).

Morphology of tendon fibroblasts from aging mice was altered when compared to fibroblasts from young mice (30). Analysis of collagen fiber alignment using polarized light microscopy showed a significant decrease in collagen fiber, and a distinctly different alignment of the aged fibril structure when compared to the mature ones. Aged mice tendons exhibited decreased collagen alignment and fibril distribution was also substantially broader in aged tendons 31, 32.

Changes of diameter collagen fibrils seem different in different aging model. Aged mice tendons exhibited more large-diameter collagen fibrils when compared to mature tendons (31). No significant decline was found in collagen fibril diameter at any location in the aging rabbit healing patellar tendons compared with those of mature rabbits (33). But in human posterior cruciate ligaments the diameter of tendons’ fibril is decreased in aging (34). And human Achiness tendon collagen fibrils had a bimodal distribution with young animals having uniformly smaller fibrils followed by a progressive increase in the mean diameter of collagen fibrils until maturation and then a decrease in diameter with further aging (6, 35, 36, 37, 38). Accordingly, diameter of the collagen fibers were higher in the 20-29 year-old group compared to younger and aging groups (37). Moreover, ultrasonography results showed that the aging supraspinatus tendons became thickened, hypoechogenic, and more likely to tear (39).

Aging also lead to more flattened cell nuclei in tendon cells. The tendon cell nuclei shape significantly changed with age as the in 1-month rats, tendon nuclei were round but became more elongated at 3 and 12 months (40). Aged mice tendons exhibited decreased collagen alignment and possessed large-diameter collagen fibrils and more elongated cells when compared to mature tendons. But the overall structures were comparable with no obvious differences in tendon architecture (31).

Changes in the composition of aging tendons

Tenocytes are the dominant among these cell types in tendons (6) and are composed of collagens, proteoglycans and other non-collagenous proteins. The most abundant tendon component is type I collagen, which constitutes about 95% of the total collagen with the remaining 5% consising of types III and V collagens (6). This composition is altered as a tendon aged. RT-PCR analysis showed mRNA expression of collagen I, III, and V were decreased in tendons of old rats, although immunostaining detected no apparent differences in collagen I and V expression at the protein level (41). These decreases were also accompanied by decreased tenocyte proliferation in the older rats (30). However recent studies have shown no change in the levels of both collagen I and III mRNA and protein in old tenocytes from rat Achilles tendons although tenocyte proliferation in old rats was significantly lower (42). Similar results were also observed in other studies where the levels of collagen I mRNA and/or protein remained the same among the Achilles tendons of young, adult and aging groups of rats (10), and supraspinatus tendons of young and old humans (43).

Investigation of the effects of aging on tenocyte proliferation and cell cycle progression showed a decline in the proliferation of tenocytes with increasing age and was also associated with the down-regulation of cellular senescence-inhibited gene and upregulation of p27 (44). Achilles tendon tenocytes from older mice was shown to have decreased cellularity, low motility and proliferation potential (30). Similarly, tenocytes from patellar tendons of aged mice also showed a significant decrease in cellularity too. Such decreased cellularity leads to a more elongate tenocytes in aging mice compared with young mice (31). Decrease in cell numbers has also been reported in aging rat tail tendons compared to young rats 40, 45. In vitro studies showed a significant decrease in cell growth and average colony size of human tenocyte-like cells from aged donors (43). These and other studies indicate the response of tendons to aging.

Aging affects ECM of tendon

Maintenance of both tendon material and structural properties is essential for function, which is achieved by a balance between matrix synthesis and degradation. Age-associated degenerative loss of functional integrity in tendons develops from cumulative effects and subtle changes in their ECM (13). ECM proteins are known to control lubricating and elastic properties of tendons, and growth factors in turn are known to regulate the expression of ECM proteins in tendons (46). Achilles tendon fibroblasts in old mice had poorly organized actin cytoskeleton and the localization of key focal adhesion proteins was also different compared to young mice (30). The importance of ECM was evident from an increased susceptibility of aged individuals to injury that results from the presence of partially degraded collagen in the matrix, which reduces the mechanical properties of tendons 47, 48.

While tendon tenocytes are responsible for synthesis of extracellular matrix proteins, the breakdown of ECM is controlled by the release of matrix metalloproteinases (MMPs) and inhibited by tissue inhibitor of metalloproteinases (TIMPs) (28). In particular, the levels of mRNAs that encode MMP-2 and -9 are significantly more abundant in tenocytes from aged rats. In addition, gelatin zymography revealed a significant increase in the enzymatic activities of MMP-2 and -9 in tenocytes with aged 10, 13 which indicate MMPs may contribute to loss of ECM. Besides aging, strain has also shown to affect MMP expression levels in tendon cells.

In contrast to increasing MMP mRNA levels in aged tendons, mRNA levels of the ECM adhesion receptor, proteoglycan 4 (PRG4), and the primary ECM protein, elastin (Eln), were lower in aged rat tendons. However, no difference was observed in the mRNA expression of connective tissue growth factor, or stromal cell-derived factor 1 between rats of different ages (46).

Aging impairs tendon stem cells

TSCs have been recently discovered in human, mouse (15), rat and rabbit 49, 50 and confirmed to play an important role in maintaining the homeostasis of the tendon. The contribution of TSC dysfunction and/or depletion on aging has not been studied well. However, a few facts are known about TCSs in aging tendons.

First, the fraction of TSCs among the total tendon cells was remarkably smaller (70%) in old than young rats evident from the number of colonies formed in culture (16). With respect to surface markers, TSCs from supraspinatus tendon were positive for the stem cell specific markers, CD29, CD44, CD73, CD90 and CD105 but negative for non-stem cell markers, CD11b, CD14, CD19 and CD34 in both young and aging groups (51). Nearly 100% of both young and aged TSPCs stained positively for three stem cell markers: nucleostemin, octamer-binding transcription factor 4 (Oct-4), and stage-specific embryonic antigen-4 (SSEA-4). No difference was observed in the expression of stem cell markers Oct-4, nucleostemin and SSEA-4 between the old and young TSCs from rats (16).

Second, the self-renewal capacity of TSCs declined with age, which accounted for the reduction in stem cell numbers in aged individuals. In addition, aged TSCs were preferentially subject to late cell cycle arrest (16), thus contributing to reduced self-renewal. While 13% of tenocyte-like cells from young donors formed adherent cell colonies, only 7 % from aged donors successfully formed colonies (43). Further, self-renewal of TSCs was regulated by Cited2, which was a multi-stimulus responsive transactivator involved in cell growth and senescence. Expressions of the mRNA and protein levels of Cited2 were reduced in aged TSCs indicating its role in the decreased self-renewal capacity of TSCs (16).

Third, the ability of TSCs to differentiate into tenocyte also diminished with aged (16). Patellar tendons from older rats (4-6 months old) had lower metabolic activity which was shown by the low 3H-thymidine and 3H-proline incorporation rates (2). This is consistent with the lower levels of tenocyte specific genes Scleraxis and Tenomodulin in old rat TSCs. However, the protein expression of Col-I, Col-III, Osteocalcin did not show significant differences between the cells of young and aging groups (51).

Finally, TSCs from aging tendons may contribute to the development of degenerative tendinopathy by undergoing aberrant differentiation into non-tenocyte (20). TSCs from supraspinatus tendon of aged donors had a significantly enhanced osteogenic differentiation potential of when compared to young donors (43). In addition, TSCs from older rats differentiated into adipocytes quicker than younger rats, which were shown by the higher mRNA levels of the adipocyte associated gene PPARy (16).

Aging affects mechanical properties of tendons

Mechanical properties of tendons are typically measured by two parameters: Young's modulus and stiffness (52). Young's modulus is an intrinsic property of a material that refers to its modulus of elasticity. It is calculated as the ratio of stress to strain along an axis. On the other hand, stiffness indicates the resistance of an elastic body to deformation by an applied force. It is typically defined as the ratio of change in tensile force to change in length of the material and therefore is an extrinsic property (52). Injured tendons in general have poor mechanical properties and tendon repairs are deemed successful only if they can re-establish the biomechanical properties of the normal tendon in the linear range.

Aging is thought to alter the biomechanical properties of tendons resulting in a functional deficit. Despite this expectation, the modulus was not significantly different between 1 and 4–5-year-old rabbits (53). In addition, both normal and repaired tissues exhibited non-linear stress–strain curves typical of collagenous materials. However, another study reported a higher tensile modulus in aging rat tendons (40). Moreover, exposure of tendons to repetitive mechanical loading also had an effect on their biomechanical properties. Tendons from aging rats had lower Young's modulus and total strain at failure than younger counterparts (52). Chronic increases in tendon loading during childhood resulted in microstructural changes which increased the tendon's Young's modulus (54). Peak stress increased from childhood to adulthood due to greater increases in strength than tendon cross-sectional area. Peak strain remained constant as a result of parallel increases in tendon length and peak elongation (48).

The elastic parameters were significantly increased by 50% in middle-aged rats (55). Similarly, in humans injury of Achilles tendon was more common in middle-aged individuals.

Age-related increases in tendon stiffness were largely attributed to increased tendon loading from weight-bearing tasks and increased plantar flexor force production. A chronic protocol enhanced the elasticity of young tendons and increased the loads in both the young and old tendons (52).

Proprioceptive senses, particularly of limb position and movement, deteriorate with aging. Current laboratory and clinical evidence suggested that aging results in preferential loss of distal large myelinated sensory fibers and receptors (56). The numbers of mechanoreceptors, especially Ruffini receptors, decreased with aging in both diminished numbers and changed morphology of mechanoreceptors in anterior cruciate ligaments of rabbit and human coracoacromial ligament 57, 58. No research reported how the loss of mechanoreceptors affected the mechanical properties of aged tendon; so further research is needed to clarify the relationship between age and impairment of mechanical properties in vivo.

Strategies to improve aging tendons

Enhance the stemness of TSCs

A decline in the tissue regenerative potential is a hallmark of aging and may be due to age-related changes in tissue-specific stem cells (59), which in younger tendons replenishes the tenocyte population. Therefore, strategies based on tendon-specific stem cells could increase the numbers of tenocytes in aged tendons. Many stem cell populations lose the capacity for self-renewal when situation of the stem cell niche changed, suggesting that the local environment plays a major role in controlling stem cell fate (60). For example, regenerative responses of adult muscle stem cells and human embryonic stem cells (hESCs) were inhibited by systemic milieu from aged individuals (61). In heterochronic tissuetransplantation studies, age of the host environment determined the regenerative outcome, as both young and old skeletal muscle explants containing differentiated and precursor cells effectively regenerated in young, but not in aged animals (61). Therefore, stem cell-based therapies for regeneration of old and dying cells should weigh the positive and negative influences of aged tissues on transplanted cells. Another alternate is to use stem cells cultured in vitro for such therapies. Recently, an increase in the stemness of TSCs was reported by culturing them in hypoxic conditions (62). Since hypoxia is in general observed in vivo, cultured TSCs could enhance the efficiency of stem cell based regenerative strategies.

ECM is another important part of TSCs niche, and therefore the balance between MMP and TIMP must be well maintained. Decellularized tendons were shown to mimic the biochemical composition of the tendon ECM during tendon tissue engineering, where the intrinsic ultrastructure of tendon tissue was preserved well 63, 64. Alternatively, a newly developed substrate material for TSCs, the engineered tendon matrix isolated from decellularized tendons, effectively expanded TSCs in vitro and enhanced repair of injured tendons in vivo

The effect of mechanical loading on tendon healing

Effects of stretch on aging tendons in vitro

Moderate mechanical loading imparts various beneficial effects on tendons. Almekinders was the first to report an in vitro model to study of the effects of repetitive strain on human tendon fibroblast (65). Mechanical stretching can modulate proliferation of human tendon fibroblasts in the absence of serum and increase the cellular production of collagen type I (66). Stretching also increased the proliferation of mouse TSCs in a stretching magnitude dependent manner with a slight increase at 4% and a further increase at 8% when compared to un-stretched TSCs. In these TSCs, the gene expression and protein production of collagen type I also increased in a stretching-magnitude-dependent manner (3). Repetitive stretching on the other hand leaded to inflammatory changes such as increase in prostaglandin E2 (PGE2) levels, deoxyribonucleic acid and protein synthesis. Moreover, release of interleukin-6 by macrophages was also enhanced suggesting that IL-6 plays a role in the response of tendons to repetitive motion (11).

Cyclical strain resulted in an age-related loss of ultimate tensile stress in tendons (13). The decreased contraction rate has been observed with increasing age, and may limit the ability of tendon cells to retighten lax tendons in older individuals (40). Elastic modulus was significantly affected by age; the aged tendons had a decreased modulus but remained significantly higher than the young control. For ultimate stress, no significant change was found in both aged and young rat tail tendon (67). Modulus increased with old age in tibialis anterior tendons of mice both at maximum tendon strain and at physiologically relevant strain (68).

Mechanical loading effects on aging tendons in vivo Treadmill running can mimic mechanical loading conditions in vivo and has been shown to have beneficial effects. uphill treadmill running in rats caused no differences in histopathological scores among young and aging groups (69). However, inflammatory changes were greater in aged rat tendons (70), while tendon diameter was not affected by the running protocol. Repetitive stretching enhanced the elastic stiffness of young tendon and the loads in both the young and old tendons (52). Different stretching protocols on various animal models have generated contradicting results and therefore should be considered with caution.

Exercise exerted its anabolic effects on tendons at least in part by increasing the proliferation of TSCs and cellular production of collagen (50). Maximal strain of the Achilles tendon was known to decrease with age. The age-related changes in human plantar flexor muscles and Achilles tendons were not similar. In particular, age-related changes in the Achilles tendon was observed in men in 30s, whereas there were no differences in muscle strength and activation levels between the 20- and 30-yr groups (71).

Both patella tendon stiffness and percentage in quadriceps maximum voluntary isometric force increased after resistance-training (72). These results indicated a faster contractile force transmission to the skeleton and suggest that strength training in old age can reverse the deteriorating effect of aging on tendon properties and function (73). Lowintensity mechanical stimuli promote the synthesis and possible rearrangement of molecules in immature tendons, whereas inactivity leaded to deleterious effects on the material properties during growth and maturation in chicken superficial digital flexor tendon model (74).

In both young and aged men, short-term immobilization impaired mechanical properties of the patellar tendon on the immobilized side, which can influence the function of the muscle–tendon complex (75). During aging there is a marked decline in muscle mass and strength which can be partly ameliorated by resistance training. Therefore, exercise is in general encouraged as it has health benefits and a feeling of well-being during the aging process (7).

Non-steroidal anti-inflammatory drugs (NSAIDS)

Traditionally, treatment of tendon injuries resulting from over use or aging involves releaving symptoms, which are mainly the pain in and around tendons. These treatments largely try to control inflammation that causes the pain. Corticosteroid injection approved by the FDA, have been used for decades in the treatment of tendinopathy. It exerts its effects by reducing the levels of pro-inflammatory mediator PGE2. In 1995, Almekinders found that nonsteroidal anti-inflammatory medications decreased PGE2 release and DNA synthesis but increased protein synthesis (11). These medications provide short-term pain relief in patients with lateral epicondylitis and shoulder impingement although the longterm efficacy of corticosteroid injections for tendinopathy has not been demonstrated.

Treatment modalities aimed at modulating inflammation have had limited success in treating chronic, painful conditions arising from overuse of tendons (76). There could be a beneficial effect through the inhibition of inflammatory mediators. The increase in PGE2 levels in injured tendons is in part induced by pro-inflammatory cytokines that play a major role in tendinopathy 12, 77. Aged tenocytes proliferation decreased significantly after ciprofloxacin treatment, aging potentiated the ciprofloxacin-mediated inhibition of migration, proliferation, and expression of type III collagen of tenocytes (78). In fact the ability of tendons to resolve inflammation was determined by assessing FPR2/ALX expression. An age-associated decline in FPR2/ALX receptor expression was found with concurrent increased PGE2 levels in injury. So aged individuals exhibit a reduced capacity to resolve inflammation via FPR2/ALX, which may present a potential mechanism for development of chronic tendinopathy and re-injury (79).

Therefore, pro-inflammatory cytokines may provide a target to prevent pain associated with tendinopathy.

The effect of growth factors

Growth factors have drawn increasing interest in the field of tendon injury and repair. In aged patients, who likely have reduced cell biological potential, growth factors augmentation may be particularly beneficial. It has been suggested that the exogenous application of growth factors could improve tendon healing.

Because Platelet-rich plasma (PRP) was thought to have beneficial effects on healing due to the presence of growth factors stored in the platelets, PRP has now being widely used in orthopedic interventions (80). In vitro and in vivo experiments have demonstrated that PRP promoted differentiation of TSCs into active tenocytes with high proliferation rates and collagen producing capability 81, 82. In addition, the autologous nature of PRP also makes it a safer and alternative option to treat tendon injuries caused by over use or aging (83). Because of questionable animal model, different pathogenetic factors and protocol of PRP, short of prospective, randomized, double-blind studies, it is difficult to get a consistent conclusion (84). But the beneficial effects of PRP can be used to its fullest if the method of PRP preparation and its application on injured or aged tendons is optimized.

Bone morphogenetic protein (BMP) activity is associated with inflammation-related induction of tendinopathy. BMP-7 led to significant increases in human rotator cuff tenocytes activity, collagen-I expression and protein synthesis when compared to BMP-2 (43). Further BMP-2 mediated PGE2 -induced reduction of proliferation and osteogenic differentiation of hTSCs (77). Because BMP-2 can lead to osteogenic differentiation of TSCs too, uses of BMP for aging-related tendinopathy need intensive research.

Transforming growth factor-β1 (TGF-β1) was thought as an essential factor in tendon physiology, however no difference in systemic TGF-β1 levels was found in serum obtained from young and elderly donors (85), TGF beta increased the incorporation of [3H]-proline and the production of types I and III collagen in aging equine tendon tenocytes (86). Insulin-like growth factor I (IGF-I), VEGF and angiogenic factors had shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing of tendon 87, 88; but there are still no results in aging tendon.

Potential therapy methods for aging tendons

The repair of injured tendons still remains a challenge and treating aged tendons is a greater challenge. Age-related changes in tendons appear to result from an imbalance between the protective/regenerative changes and the pathologic responses. Therefore, we suggest that potential therapy methods should combine various treatment options.

Mechanical loading combined with surgery

A great deal of evidence is not available for the best treatment for aging tendons. Surgery is often considered a last option in the treatment of tendinopathy after exhausting all non-operative options. The most commonly described procedure is surgical debridement of tendon or peritendinous tissue followed by additional repair or augmentation (89). Chronic tendinopathy can be treated with debridement and/or decompression although these procedures had high recurrence and did not completely recover function. Exercise was another safer option and exerts anabolic effects on tendons by increasing the proliferation TSCs and TSC-related cellular production of collagen (50). Strength training in aged individuals can also reverse the deteriorating effect of aging on tendon properties and function 73, 90. For these reasons, mechanical loading before and after surgery can be recommended for a successful outcome. However, training and stretching during the inflammatory phase should be avoided to minimize disruption of the healing process although controlled mobilization after the inflammatory phase could enhance the quality of healing tendons.

Stem cells and growth factors

Tendon healing is often impaired in the elderly (91). This poor response may be due to age-related alterations in the cell and matrix composition of the tissue. In addition, most treatment measures are optimized for young adults and may not be optimal for treating older individuals. Although the number of stem cells declines dramatically with aging, studies on rabbit MSCs have shown that they aging does not reduces their benefits for tendon repair therapy. A number of studies have clearly shown that TSCs maturation along the tenocyte lineage came at the expense of adipogenesis and vice versa. During aging, this balance increasingly favors the formation of adipocytes 9, 92 leading to lower numbers of tenocytes. This can be partly reversed by the application of growth factors that could induce aging TSCs to differentiate into tenocytes 66, 93, 94. A practical method to introduce an assortment of growth factors in to a tendinous area was through the injection of PRP or autologous blood. Although no FDA-approved treatments are currently available, application of stem cells and growth factors for the treatment of degenerative conditions of the musculoskeletal system such as tendinopathy is very appealing.

Concluding remarks

Age-related changes in structural and mechanical properties may predispose tendons to injury (3). We ascribed these age-related changes to the loss of TSCs. Current treatment methods were not effective in treating age-related tendon disorders. A major reason for this was due to our incomplete understanding of age-related tendinopathy. Thus, there was an urgent need to better understand the changes of biomechanics and characters of tendons during the aging process to highlight causes and improve the treatment of age-dependent degenerative tendon diseases.

With aging, the stemness of TSCs and tenocyte proliferation decreases. Differentiation of TSCs into non-tenocyte cell lineages 9, 50, 92 and ECM degradation occur simultaneously. These changes decreased collagen alignment and increase large-diameter collagen fibrils and elongate cells when compared to young tendons (31). Changes of aged tendon structure leaded to a functional deficit directly (40). While surgery is often considered a last option to treat age-related tendon disorders, it effectively alleviated the symptoms. We proposed that moderate mechanical loading training before/after surgery could enhance the quality of healing tendons (20). A combination of mechanical loading, surgery, and stem cell and growth factor based treatment strategies will profoundly improve age-related tendon disorders.