1Department of Biomedical Engineering, 2Department of Orthopaedics, 3Department of Cell and Molecular Physiology, and 4Curriculum in Applied and Material Sciences, University of North Carolina at Chapel Hill, Chapel Hill 27599; and 5Flexcell International Corporation, Hillsborough, North Carolina 27278
Submitted 19 February 2004 ; accepted in final form 9 June 2004
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ABSTRACT |
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-adrenoceptors; fibroblasts; catecholamines; tenocytes
Adrenoceptors are G protein-linked cell membrane receptors that are divided into three main families: 1,
2, and
. Stimulation of
1-adrenoceptors can liberate inositol trisphosphate, diaclyglycerol, arachidonic acid, and phosphatidic acid and produce changes in cAMP and intracellular Ca2+ concentration ([Ca2+]ic) (12, 17, 22, 43, 51). Stimulation of
2-adrenoceptors can inhibit (block or close) Ca2+ channels, open potassium channels, and inhibit adenyl cyclase (12, 17, 43). However, data also indicate that
2-adrenoceptors are linked to Ca2+ influx (43). Stimulation of
-adrenoceptors activates adenyl cyclase and thus increases cAMP (12).
There are three 1-adrenoceptor subtypes:
1A,
1B, and
1D, the functions of which are widespread and the actions of which can depend on which cell type expresses them and the anatomical location (see Refs. 15, 17, 32, and 49 for reviews). For instance, stimulation of
1B-adrenoceptors on rat aorta adventitial fibroblasts induces proliferation, whereas
1A-adrenoceptors mediate this action on medial smooth muscle cells. In contrast,
1D-adrenoceptors mediate constriction of this vessel (52). With the vascular system, all
1-adrenoceptor subtypes are important for controlling contraction, vessel tone, and blood pressure.
Adrenergic nerves (i.e., containing tyrosine hydroxylase and neuropeptide Y immunoreactivity) are associated with the microvasculature within and around tendons and in the paratenon (2). Sympathetic, hemodynamic, and biomechanical factors modulate blood flow in tendon and ligament as in most other tissues (39, 48). In several cell types, NE or epinephrine induces an increase in [Ca2+]ic through both Ca2+ influx and/or release from intracellular stores (11, 29, 31, 33, 38, 41, 44).
Evidence of adrenoceptors in connective tissues is found in UMR-106 cells, a rat osteosarcoma cell line, wherein cAMP and intracellular Ca2+ increased in response to NE (10, 33). The Ca2+ response was linked to both 1- and
-adrenoceptors. Ca2+ release from bone is also modulated by
- and
-adrenoceptors (47). Furthermore, adrenoceptors were unexpectedly found in relatively high abundance in vascular adventitial fibroblasts (20) that migrated and proliferated in response to
1-adrenoceptor stimulation (20, 52, 53). Mouse embryonic fibroblasts (3) as well as rat cardiac fibroblasts (35) also proliferated in response to
-adrenoceptor stimulation. However, no published data implicate a particular adrenoceptor subtype expressed in tendon cells.
Within tendons, an endotenon is continuous with the epitenon that encases the whole tendon. The endotenon, a sheet of loose connective tissue, binds together the blood vessels, nerves, and collagen fascicles. Thus the surface cells of the epitenon are more likely to be exposed to NE under normal physiological conditions than the internal fibroblasts that reside amidst the collagen fibrils. NE may have a greater effect on these epitenon cells than the internal fibroblasts. However, both cell groups would be exposed to NE during traumatic injury. Therefore, it was hypothesized that avian tendon surface epitenon cells (ATSC) and internal fibroblasts (ATIF) express adrenoceptors and respond to NE with an increase in [Ca2+]ic.
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METHODS |
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Tendon explant isolation. To evaluate the Ca2+ response in tendon explants, the FDPs were removed from the middle toe of both feet of 5- to 6-wk-old White Leghorn chickens (Cackle Hatchery, Lebanon, MO). Each FDP was cut into three sections, labeled with fura 2-acetoxy methylester (fura 2-AM; Molecular Probes, Eugene, OR), and then potted in 1% agarose gel (to stabilize the tendon during addition of the agents) in Earle's balanced salt solution (EBSS) with 20 mM HEPES, pH 7.2, 1.80 mM calcium chloride, and 0.8 mM magnesium sulfate (Tissue Culture Facility, Chapel Hill, NC).
Total RNA isolation from tissue. Total RNA was isolated from tissue samples (15 g wet wt each of brain, pectoralis major muscle, spleen, kidney, lung, heart, FDP tendon, metatarsal bone, liver, and cartilage from the tip of the metatarsal bone) from six 52-day-old White Leghorn chickens (Goldkist, Sanford, NC) as previously described by Banes et al. (7). Briefly, samples were weighed (1 g wet wt each), frozen in liquid nitrogen, pulverized, and solubilized with RNA Stat-60 (Tel-Test B, Friendwood, TX). Samples were homogenized with a Polytron (Fisher Scientific, Pittsburgh, PA), treated with chloroform, and vortexed. After sedimentation, the supernatant fluid was extracted with RNA Stat-60 and chloroform, mixed, and sedimented. Then, 0.7 vol of isopropanol was added to the supernatant fluid and sedimented. Pellets were reconstituted in 1 ml of diethylpyrocarbonate-treated deionized water.
Total RNA was also isolated from the following tissue samples (0.21.2 g wet wt) from six 122-day-old White Leghorn chickens (Cackle Hatchery): proximal and distal FDP, proximal and distal extensor digitorum longus, anterior cruciate ligament, and the medial and lateral menisci (distal denotes the toe and proximal the ankle regions of the chicken foot). After being weighed, samples were pulverized in liquid nitrogen and solubilized in TRIzol (1 ml/100 mg of tissue; GIBCO). Samples were homogenized with a Polytron, incubated at room temperature for 5 min, and then treated with 1-bromo-3-chloropropane (0.1 ml/ml TRIzol; Molecular Research Center, Cincinnati, OH). Samples were mixed, incubated at room temperature for 3 min, and sedimented at 7,200 g at 4°C for 15 min. The aqueous phase was collected, treated with isopropanol (0.5 ml/ml TRIzol), and precipitated at 14,000 g at 4°C for 10 min. Pellets were washed with an equal volume of 70% ethanol and sedimented at 14,000 g at 4°C for 5 min. Pellets were reconstituted in 100 µl of RNase-free water.
Quantitative RT-PCR.
Total RNA was used in quantitative RT-PCR experiments to determine the presence of mRNA for 1-adrenoceptor subtypes in the avian tissues. In the RT reaction, 10 µg total RNA were mixed with the following in final concentrations: 1 mM each of 2-deoxynucleoside 5-triphosphates, 1 ng/µl random hexamers, 0.8 units/µl RNaseOUT recombinant ribonuclease inhibitor, 0.01 M dithiothreitol, 4 units/µl Superscript II RNase RT, and PCR buffer containing 50 mM Tris·HCl, 75 mM KCl, and 3 mM MgCl2 (Invitrogen, Carlsbad, CA; GIBCO). The RT mix was incubated at 25°C for 10 min and then heated at 42°C for 120 min, at 99°C for 5 min, and at 5°C for 5 min. The following sequences were used as sense and antisense adrenoceptor primers, respectively (20):
1A-adrenoceptor (204 bp), 5'-CGAGTCTACGTAGTAGCC-3' and 5'-GGCTTGGCAGCTTTCTTC-3' [there is 1 base pair difference (underlined) in the cloned avian sequence and the sequence for rat published by Faber et al. (20)];
1B-adrenoceptors (201 bp), 5'-ATCGTGGCCAAGAGGACC-3' and 5'-TTTGGCTGCTTTCTTTTC-3'; and
1D-adrenoceptors (218 bp), 5'-CGCGTGTACGTGGTCGCAC-3' and 5'-CTTGGCAGCCTTTTTC-3'. In the PCR reaction, the cDNAs from the avian tissues were mixed with the following agents at final concentrations: 0.05 units/µl Platinum Taq DNA polymerase (Invitrogen), 0.5 µM internal standard, 0.5 µM of sense and antisense primers, PCR buffer containing 16 mM (NH4)2SO4, 67 mM Tris, pH 8.8, 0.1 mM each of 2-deoxynucleoside 5-triphosphates, 2.25 mM MgCl2, and 0.2 nl Tween 20. The cDNAs from the tissue of the 52-day-old White Leghorn chickens (including the spleen, muscle, liver, kidney, heart, lung, cartilage, bone, tendon, and brain) and the 112-day-old White Leghorn chickens (including proximal and distal FDP, proximal and distal extensor, anterior cruciate ligament, and meniscus) were amplified with QuantumRNA 18s rRNA (Ambion, Austin, TX) as the internal standard. The Competimer technology controls for the amplification of 18s cDNA, thus keeping 18s rRNA within the same linear range as the mRNA of interest. Samples were initially denatured at 94°C for 5 min followed by 35 cycles of denaturing, annealing, and extension at 94°C, 62°C, and 72°C, respectively, for 30 s each and a final extension at 72°C for 5 min in a Perkin-Elmer 2400 thermocycler (Wellesley, MA). Amplification products were separated in 1.8% agarose gels for 22 min at 93 V (20 mA). Gels were stained with ethidium bromide (Fisher Scientific) and photographed with a Polaroid camera (Waltham, MA). The relative band intensity was quantified by image analysis.
Cloning.
Primers for rat 1-adrenoceptors were used to amplify mRNA in the bone tissue from 52-day-old White Leghorn chickens. The cDNAs were extracted from the gel using a QIAquick gel extraction kit and purified with a QIAquick PCR purification kit (Qiagen, Valencia, CA). The cDNAs were ligated using an Original TA cloning kit and transformed into TOP10F Escherichia coli cells using a One Shot kit (Invitrogen). Plasmid DNA was isolated from bacteria using a QIAwell 8 Ultra Plasmid kit (Qiagen) and then sequenced. Sequences were submitted to GenBank.
Intracellular Ca2+ measurements. On day 6 after plating, ATSC and ATIF were rinsed twice with EBSS. The cells were then incubated in the dark at room temperature in 2.5 or 5 µM fura 2-AM with 0.1% Pluronic-127 (Molecular Probes) for 4560 min. After incubation, the cells were rinsed twice in EBSS to remove any unincorporated fura 2-AM. The six-well dish was mounted on the stage of an Olympus BX-51 upright fluorescence microscope (Melville, NY) equipped with a 40x water immersion ultraviolet objective lens, a Sutter Lambda DG4 wavelength switcher and light guide (Novato, CA), and a CoolSnap digital camera (Roper Scientific, Trenton, NJ). Image analysis software (ISee Imaging Systems, Raleigh, NC) was used to quantitate the changes in [Ca2+]ic. The ratio method, with 340 (bound)- to 380 (free)-nm excitation and 510-nm and above emission, was used to convert the fluorescence emission intensity of the labeled tendon cells to Ca2+ ion concentration by comparison to known Ca2+ standards (23). All cells in a field of view [977 cells in 2-dimensional (2-D) cultures, 12151 cells in explants] were selected and outlined, and the pixel intensity relating to Ca2+ concentration was quantified for each cell. Background images were obtained from an area without cells at the start of each experiment. Background pixel values were subtracted from each image to correct for nonuniformity due to variation in the fluorescence excitation beam across the field.
Treatment with NE and differentiation of adrenoceptor subtypes. Avian tendon cells were exposed to 0.01, 0.03, 0.1, 0.3, 1, or 10 µM NE (n = 28 isolations with 212 replicates). Cells in any one specimen were exposed to only one NE concentration. Basal Ca2+ levels were determined by averaging the [Ca2+]ic over 3060 s before NE treatment. For 2-D cultures, a cellular response was mathematically represented as an increase in [Ca2+]ic that averaged three standard deviations above the basal level of the cell. Avian FDP explant sections were treated with 1 or 10 µM NE, and an FDP section from the opposing leg was treated with 1, 10, or 100 µM ATP as a positive control. Each section received only one drug concentration. For explants, a cellular response was mathematically represented as an increase in [Ca2+]ic that averaged two standard deviations above the basal level, since there was a large change in the background across the data set from the autofluorescence of collagen. The response was averaged from the initial increase in [Ca2+]ic after treatment until the Ca2+ signal output returned to a steady level.
ATSC and ATIF were also exposed to 1 µM NE in EBSS that contained no exogenous Ca2+ to differentiate between extracellular Ca2+ influx vs. release of Ca2+ from intracellular stores (n = 4 isolations with 26 replicates). Cells were incubated in EBSS without Ca2+ for at least 30 min before NE treatment. To differentiate among the possible adrenoceptors activated by NE, ATIF (n = 34 isolations with 34 replicates) were incubated in 100 nM of 1A-adrenoceptor antagonist KMD-3213 (kindly proved by Dr. Y. Kurashina and Kissei Pharmaceutical, Matsumoto City, Japan),
1B-adrenoceptor antagonist AH-11110A,
1D-adrenoceptor antagonist BMY-7378, or
2-adrenoceptor antagonist RX-821002 or 1 µM
-adrenoceptor antagonist propranolol for 30 min before exposure to NE. The concentrations of the antagonists were within the selective concentration for these compounds (52, 53). All pharmacological agents were purchased from Calbiochem (San Diego, CA), Tocris (Ballwin, MO), or Sigma unless otherwise noted.
Statistical analysis. Data were analyzed using JMP (SAS Institute, Cary, NC) or SigmaStat (SPSS, Chicago, IL) and subjected to a Student's t-test, nonparametric t-test, or one-way ANOVA with a post hoc test, where appropriate, to determine significance between and among groups (P < 0.05). Data are presented as means ± SE. About 1.1% of all cells analyzed in 2-D cultures had a slow gradual increase in [Ca2+]ic over the entire period of data collection. Because these cells did not satisfy the defining criteria of a responding cell, they were considered to be nonresponders.
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RESULTS |
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DISCUSSION |
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Tendon cells significantly responded to NE concentrations >0.1 µM. Physiological NE concentration can depend on nearness to adrenergic nerves and level of activity where concentrations are in the micromolar range (8). If the tissue is noninnervated, then the NE concentration depends on plasma concentrations. Basal plasma NE is 23 nmol/l and can increase 10-fold during exercise (25, 30). Injury and inflammation can increase local NE release by locally activating nerves (13). In addition, ischemia can increase NE efflux and thus raise tissue concentrations to micromolar levels (45). Thus the response to NE within tendon cells in vitro is within physiological and/or pathophysiological ranges.
NE induced either an immediate or a biphasic Ca2+ signal. The majority of tenocytes had an immediate Ca2+ transient upon stimulation by NE that rapidly returned to basal levels. In a small percentage of avian tendon cells as well as in astrocytes (41) and hepatocytes (50), a biphasic Ca2+ response was also observed. This response is characterized by an initial Ca2+ transient followed by secondary Ca2+ oscillations. In Chinese hamster ovary cells transfected with 1A-adrenoceptor (29) and rat afferent arterioles (44), the Ca2+ response is characterized by an initial Ca2+ peak followed by a secondary sustained plateau increase in [Ca2+]ic. In UMR-106 cells (33), the secondary phase was characterized by a slow rise in [Ca2+]ic. This secondary oscillatory response in the avian cells is dependent on Ca2+ influx as illustrated by the loss of oscillations in the absence of exogenous Ca2+. Similar losses of the biphasic response were also seen in Chinese hamster ovary cells, afferent arterioles, and UMR-106 cells.
Because the source of Ca2+ can originate from intracellular stores or from Ca2+ influx, extracellular Ca2+ was removed from the bathing solution and cells were then stimulated with NE. The Ca2+ response in the absence of exogenous Ca2+ was attenuated but not completely abolished, indicating that NE induced the release of Ca2+ from both intracellular stores and influx of Ca2+ through ion channels in the plasma membrane. In addition, the NE-induced Ca2+ rise in tendon cells appeared to be mediated by 1A-adrenoceptor because a specific antagonist for this adrenoceptor reduced the overall percentage of cells responding to NE as well as the increase in [Ca2+]ic. The reduced response to 0.03 µM NE in the presence of RX-821002 indicated that there may be a small contribution from
2-adrenoceptors. There was a trend toward reduction in the percentage of cells responding to NE (Fig. 6) and in the rise in [Ca2+]ic (Table 1) in the presence of the
1B-,
1D-, and
2-adrenoceptor antagonists (not significant by 1-way ANOVA). This may reflect, in the case of AH-11110A and BMY-7378, partial inhibition of
1A-adrenoceptor population by these compounds. Although these agents are the most selective
1B- and
1D-adrenoceptor antagonists available, they are not fully "specific." BMY-7378 has a 267-fold selectivity for
1D-adrenoceptors over the
1A- and
1B-adrenoceptors (see Ref. 53). AH-11110A has only a 32- and 26-fold selectivity for
1B-adrenoceptors over the
1A- and
1D-adrenoceptors, respectively (see Ref. 53). KMD-3213 is 56- and 583-fold selective for
1A- over
1D- and
1B-adrenoceptors, respectively (see Ref. 53). RX-821002 and propranolol have 1,000-fold or more selectivity for
2- and
-adrenoceptors, respectively, over
1-adrenoceptors. Thus, given the limitations of available antagonists, our data suggest that
1A-adrenoceptors are primarily responsible for NE activation of avian tendon fibroblasts, with a potential small contribution by
2-adrenoceptors.
In addition to stimulation of tenocytes in vitro, cells within whole tendon explants responded to NE. However, only a low percentage of the cells responded. This low responsiveness could be due to the anatomical location of the tenocytes within the FDP. Cells in closer proximity to blood vessels or nerves could have a greater response than those cells more isolated from the sources of NE. However, we found that epitenon surface cells, which are closely associated with blood vessels and nerves, did not respond differently from internal fibroblasts from the tendon midsubstance. The age of the tissue (56 wk old) could also account for the lower response. Cells in avian aortic smooth muscle respond to NE with the greatest Ca2+ response seen in 12- to 18-wk-old chickens and less in older (2037 wk old) animals (42). Muscle from younger (58 wk old) chickens did not respond to NE with a Ca2+ transient. In addition, rat myocyte adrenoceptor coupling to L-type Ca2+ channels changes during development (37). Explant tissue may present fewer adrenoceptor-expressing cells. Alternatively, the explant model itself may decrease responsiveness to NE by reducing NE diffusion or increasing degradation.
The importance of adrenergic activation in tenocytes is unknown. Within most connective tissues, it is believed that sympathetic nerves control blood flow through the tissues, since most of the nerves are located in or around blood vessels (2, 9, 39). Adrenoceptors also may be involved in endocrine regulation of connective tissues. Both cartilage and meniscus have little vasculature and nerves but express the mRNA for 1A- and
1B-adrenoceptors (see RESULTS). Only about one-third of the meniscus is innervated and vascularized (16). Cartilage is aneural and avascular, relying on diffusion from the synovial fluid for nutrition, metabolites, and waste removal. However, the synovium is sympathetically innervated (27). NE is also secreted from cells in synovial tissue taken from arthritic knees (40). Thus NE or circulating adrenaline could diffuse from blood vessels into the synovial fluid and stimulate adrenoceptors in meniscus or cartilage cells. Finally, adrenoceptors may be involved in the response to healing after injury. In rheumatoid arthritis, tyrosine hydroxylase-positive nerve fibers were reduced, but the density of tyrosine hydroxylase-positive cells, which spontaneously secrete NE, was increased. Furthermore, NE (105 M) reduced the secretion of inflammatory cytokines in synoviocytes from patients with arthritis (40). Thus NE may play a role in modulating inflammation.
Sympathetic efferent nerves corelease neuropeptides and neurotransmitters. Neuropeptide Y is released with NE. In tendon, recent data have indicated that neuropeptides may be important in healing. Ackermann and colleagues (1) reported that in Achilles tendons, autonomic reinnervation was low up to 4 wk postrupture while the greatest increase occurred around 68 wk postrupture. Neuropeptide Y-positive nerve fibers were observed in the surrounding connective tissue and tendon proper, mainly in association with the vasculature. In addition, within the synovial fluid of arthritic joints, both sensory and autonomic neuropeptides were elevated (4, 26, 34). Neuropeptide Y also promotes wound healing and angiogensies (18). Thus autonomic neuropeptides may act locally alone or with NE to modulate the response to healing and perhaps promote the growth of new vasculature within the healing tendon.
During flexor tendon healing, the epitenon surface cells and even synovial sheath cells, where present, initiate the repair process (21, 24, 28, 36). In addition, blood vessels, and possibly nerves, may aid in healing (36). In avian tendons subjected to trauma, collagen synthesis was decreased in partially devascularized tendons compared with those tendons allowed to heal with the blood supply intact (6). It has also been shown that vascular adventitial fibroblast proliferation was induced by prolonged stimulation of 1-adrenoceptors by NE in the intact vascular wall, and this growth was further augmented after injury (52). In addition, NE and growth factors synergized to promote migration of adventitial fibroblasts (53). Thus, in a similar fashion to adventitial fibroblasts, the migration of tendon cells into a wound and the growth of new tissue during repair could be augmented by adrenergic stimulation. Indeed, stimulation of the mitotic pathway in most cells by growth factors and certain G protein-coupled agonists involves a rise in intracellular Ca2+ early in the signaling pathway. Therefore, activation of adrenoceptors, mainly
1, with a concomitant rise in [Ca2+]ic may be involved in a maintenance function as well as a healing response in tendon.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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