Summary While there is a significant amount of information available on the clinical presentation(s) and pathological changes associated with tendinopathy, the precise aetiopathogenesis of this condition remains a topic of debate. Classically, the aetiology of tendinopathy has been linked to the performance of repetitive activities (so‐called overuse injuries). This has led many investigators to suggest that it is the mechanobiologic over‐stimulation of tendon cells that is the initial stimulus for the degradative processes which have been shown to accompany tendinopathy. Although several studies have been able to demonstrate that the in vitro over‐stimulation of tendon cells in monolayer can result in a pattern(s) of gene expression seen in clinical cases of tendinopathy, the strain magnitudes and durations used in these in vitro studies, as well as the model systems, may not be clinically relevant. Using a rat tail tendon model, we have studied the in vitro mechanobiologic response of tendon cells in situ to various tensile loading regimes. These studies have led to the hypothesis that the aetiopathogenic stimulus for the degenerative cascade which precedes the overt pathologic development of tendinopathy is the catabolic response of tendon cells to mechanobiologic under‐stimulation as a result of microscopic damage to the collagen fibres of the tendon. In this review, we examine the rationale for this hypothesis and provide evidence in support of this theory.

αKlotho is thought to activate the epithelial calcium channel Transient Receptor Potential Vanilloid-5 (TRPV5) in distal renal tubules through its putative glucuronidase/sialidase activity, thereby preventing renal calcium loss. However, αKlotho also functions as the obligatory co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived phosphaturic hormone. Here, we show that renal calcium reabsorption and renal membrane abundance of TRPV5 are reduced in Fgf23 knockout mice, similar to what is seen in αKlotho knockout mice. We further demonstrate that αKlotho neither co-localizes with TRPV5 nor is regulated by FGF23. Rather, apical membrane abundance of TRPV5 in renal distal tubules and thus renal calcium reabsorption are regulated by FGF23, which binds the FGF receptor-αKlotho complex and activates a signaling cascade involving ERK1/2, SGK1, and WNK4. Our data thereby identify FGF23, not αKlotho, as a calcium-conserving hormone in the kidney.

Dissections of 12 formalin-fixed ostriches were performed to give anatomical descriptions of the muscles and tendons of the pelvic, femoral, tibiotarsal, tarsometatarsal and digital regions. In the pelvic limb of the ostrich, 36 muscles can be determined. The ostrich lacks those muscles to the first and second toes (with exception of the M. flexor hallucis longus), which can be found in birds with four toes. The Mm. iliotrochantericus medius, plantaris, extensor proprius digiti IV and adductor digiti IV, which are present in other birds, are also absent, whereas the Mm. pectineus and femorotibialis accessorius additionally occur in the ostrich. The Pars supramedialis is a tendineous part of the M. gastrocnemius, on which the Mm. flexor cruris lateralis and flexor cruris medialis insert by means of a fascial sheet. The caudal part of the M. iliofibularis terminates within the caudal aspect of the superficial fascia cruris. The caudal heads of the Mm. flexor perforatus digiti III and flexor perforatus digiti IV as well as the M. flexor hallucis longus have a common origin on the Fossa poplitea of the femur. The lateral head of the M. flexor perforatus digiti IV and the femoral head of the M. flexor perforans et perforatus digiti III originate on the tendon of origin of the Caput laterale of the M. flexor perforatus digiti III. Furthermore, the last named tendon fuses with the tendon of insertion of the M. ambiens. The M. extensor proprius digiti III originates on a plate-like fascial sheet part of the dorsal joint capsule of the intertarsal joint.

No abstract

Matrix metalloproteinase inhibitors may play a supportive role in the treatment of tendinopathy by limiting the MMP-mediated degradation of the extracellular matrix.

Tendon cells respond to mechanical loads. The character (anabolic or catabolic) and sensitivity of this response is determined by the mechanostat set point of the cell, which is governed by the cytoskeleton and its interaction with the extracellular matrix. To determine if loss of cytoskeletal tension following stress deprivation decreases the mechanoresponsiveness of tendon cells, we cultured rat tail tendons under stress-deprived conditions for 48 hours and then cyclically loaded them for 24 hours at 1%, 3%, or 6% strain at 0.17 Hz. Stress deprivation upregulated MMP-13 mRNA expression and caused progressive loss of cellmatrix contact compared to fresh controls. The application of 1% strain to fresh tendons for 24 hours inhibited MMP-13 mRNA expression compared to stress-deprived tendons over the same period. However, when tendons were stressdeprived for 48 hours and then subjected to the same loading regime, the inhibition of MMP-13 mRNA expression was decreased. In stress-deprived tendons, it was necessary to increase the strain magnitude to 3% to achieve the same level of MMP-13 mRNA inhibition seen in fresh tendons exercised at 1% strain. The data suggest loss of cytoskeletal tension alters the mechanostat set point and decreases the mechanoresponsiveness of tendon cells.

Apoptosis (programmed cell death) has been identified as a histopathologic feature of tendinopathy. While the precise mechanism(s) that triggers the apoptotic cascade in tendon cells has not been identified, it has been theorized that loss of cellular homeostatic tension following microscopic damage to individual tendon fibrils could be the stimulus for initiating the pathologic events associated with tendinopathy. To determine if loss of homeostatic tension following stress deprivation could induce apoptosis in tendon cells, rat tail tendons were stress-deprived or cyclically loaded (3% strain at 0.17 Hz) for 24 hours under tissue culture conditions. Caspase-3 (an upstream mediator of apoptosis) mRNA expression was evaluated using quantitative polymerase chain reaction and caspase-3 protein synthesis was identified using immunohistochemistry. Apoptotic cells were identified histologically using an antibody for single-stranded DNA. Stress deprivation for 24 hours resulted in an increase in caspase-3 mRNA expression when compared to fresh controls or cyclically loaded tendons. Stress deprivation also increased the percentage of apoptotic cells (10.59% +/- 2.80) compared to controls (1.87% +/- 1.07) or cyclically loaded tendons (3.73% +/- 0.87). These data suggest loss of homeostatic tension following stress deprivation induces apoptosis in rat tail tendon cells.

Cytoskeletal tensional homeostasis is known to be an important factor in controlling catabolic gene expression in tendon cells. Loss of cell tension in lax rat tail tendon fascicles (RTTfs) has been associated with an upregulation of MMP-13 gene expression and protein synthesis. To determine the role of the actin cytoskeleton in re-establishing tensional homeostasis in lax tendons, RTTfs were allowed to freely contract in vitro for 8 days. The cultured RTTfs contracted rapidly, reaching 50% of their initial length by 3 days. This contraction was associated with the presence of a-smooth muscle actin positive cells within the tendon. Disruption of the actin network by cytochalasian D caused an immediate and significant elongation of the contracted RTTfs. Subsequent removal of the cytochalasian D re-initiated the contraction process. When lax RTTfs were allowed to contract between fixed clamps in culture and become taut, they demonstrated a marked decrease in MMP-13 staining intensity when compared to freely contracting RTTfs. The ability of native tendon cells to contract lax tendons and re-establish their homeostatic ''set point'' with respect to collagenase production may be an important mechanism in the recovery of tendons elongated by injury, surgical positioning, or cyclic, viscoelastic creep secondary to repetitive exercise. ß