Using stem cells to repair torn tendons
Weekend athletes who overexert themselves running or playing basketball may one day reap the benefits of research that shows adult stem cells can make new tendon tissue. Researchers Dan Gazit and colleagues at Hadassah Medical Center in Israel engineered mouse mesenchymal stem cells (MSCs), which reside in the bone marrow and fat tissue, to express a protein called Smad8 and another called BMP2, each involved in the formation of bone and cartilage. When the researchers filled small sponges with these cells and implanted the sponges into torn Achilles tendons of rats, they found that the cells not only survived the implantation process, but were recruited to the site of the injury and able to repair the tendon for at least 7 weeks after implantation. The cells changed their appearance to look more like tendon cells (tenocytes), and significantly increased production of collagen, a protein critical for creating strong yet flexible tendons and ligaments. Tendon tissue was detected using a special type of imaging known as proton DQF MRI, which recognizes differences among collagen-containing tissue such as tendon, bone, skin, and muscle. The authors note that BMP and Smad proteins are involved in other tissues such as nerve and liver, suggesting that this type of delivery technology may be helpful for other degenerative diseases. The study appears in the April issue of the Journal of Clinical Investigation.
In an accompanying commentary, Dwight A. Towler and Richard Gelberman from Washington University School of Medicine in St. Louis, states that "given our limited understanding of how MSCs become tenocytes, the recent progress demonstrated in these studies is quite remarkable and may be potentially useful in cell-based therapeutic approaches to musculoskeletal injuries."
TITLE: Neotendon formation induced by manipulation of the Smad8 signaling pathway in mesenchymal stem cells
AUTHOR CONTACT: Dan Gazit
Hebrew University–Hadassah Medical Center, Jerusalem, Israel
Phone: 972-2-6757627; Fax: 972-2-6757628; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=22689
TITLE: The alchemy of tendon repair: a primer for the (S)mad scientist
AUTHOR CONTACT: Dwight A. Towler
Washington University School of Medicine, St. Louis, Missouri, USA
Phone: (314) 454-7434; Fax: (314) 454-8434; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=28320
No more Mr. Nice Guy: why having a big heart is dangerous to your health
Increased signaling through a protein called Gq in heart cells (called myocytes) is thought to be involved in the formation of an enlarged heart (hypertrophy) and the resulting heart failure. Thus it is surprising that patients with high blood pressure who receive drugs that block alpha1-adrenergic (alpha1A/B) receptors, which signal through Gq, demonstrate a two-fold higher risk of developing heart failure, compared to patients taking a diuretic. Now, in a new study in the April issue of the Journal of Clinical Investigation, researcher Paul C. Simpson and colleagues at the San Francisco VA Medical Center in California examine how this occurs, by studying cardiac hypertrophy development in mice genetically modified to no longer express alpha1A/B receptors. The researchers found that, compared to normal mice, these alpha1A/B "knockout" (ABKO) mice demonstrated rapid heart failure and death following a surgical procedure to induce heart failure. In addition, the ABKO animals that did survive demonstrated higher rates of myocyte death as well as elevated fibrosis, or scarring, of the heart tissue. The study suggests that alpha1A/B and Gq signaling are specifically necessary for a normal response to increased pressure on the heart, and is part of a molecular signaling program used by the heart to adapt to stress.
In an accompanying commentary, Stephen B. Liggett from the University of Maryland School of Medicine in Baltimore notes that, "although previous studies have suggested that approaches that decrease this signaling might be protective against the development of heart failure or be beneficial in treatment, the data obtained from this study of alpha1A/B knockout mice provide support for the potential deleterious effects of alpha1-adrenergic blockade."
TITLE: alpha1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload
AUTHOR CONTACT: Paul C. Simpson
San Francisco VA Medical Center, San Francisco, California, USA
Phone: (415) 221-4810 ext. 3200; Fax: (415) 379-5570; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=22811
TITLE: Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify
AUTHOR CONTACT: Stephen B. Liggett
University of Maryland School of Medicine, Baltimore, Maryland, USA
Phone: (410) 706-6256; Fax: (410) 706-6262; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=28234
The heart teams with the kidney to control blood pressure
To control blood pressure, the kidney has evolved a mechanism called the renin-angiotensin system (RAS), in which the protein angiotensinogen is sequentially cleaved by renin (then by another enzyme called ACE) to form the biologically active peptide, angiotensin II (AngII). The secretion of renin is tightly linked to salt intake and the pressure inside the kidney, suggesting that the RAS is central to controlling body fluid volume and blood pressure. Now, in a study appearing in the April issue of the Journal of Clinical Investigation, researcher Roberto Levi and colleagues at Weill Medical College of Cornell University, New York report that cells called mast cells, known to be involved in asthma and allergy, also produce renin. The authors studied isolated guinea pig hearts and found that cardiac mast cells can release renin, and that this release results in the formation of angiotensin in sufficient amounts to cause disease-associated events such as release of norepinephrine (a stress hormone involved in the "fight or flight" response) and cardiac arrythmias (irregular heartbeat). The researchers confirmed that the angiotensin was formed through the action of renin by treating the hearts with an inhibitor of renin, which abolished angiotenisn formation. The researchers confirmed these results using hearts obtained from mice. Production of renin by cardiac mast cells represents a novel mechanism for regulating RAS. The authors note that these findings imply that mast cell-derived renin may be a useful therapeutic target for cardiac dysfunctions associated with arrhythmias, cardiac death, heart attack, and heart failure.
In an accompanying commentary, Thomas M. Coffman from the Durham VA Medical Center in North Carolina states that "although the precise basis for control of renin in mast cells is not clear, this will be a critical area for future research. This discovery suggests a distinct pathway for activation of the RAS that may have a particular impact in the pathogenesis of chronic tissue injury as well as more acute pathology such as arrhythmias in the heart." He summarizes by stating that, "the finding that mast cells produce renin raises the possibility of an alternate mechanism for regulation of the RAS, controlled by inflammatory mechanisms likely to be quite different from those that regulate renin production in the kidney."
TITLE: Cardiac mast cell–derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/ reperfusion
AUTHOR CONTACT: Roberto Levi
Weill Medical College of Cornell University, New York, New York USA
Phone: (212) 746-6223; Fax: (212) 746-8835; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25713
TITLE: A new cardiac MASTer switch for the renin-angiotensin system
AUTHOR CONTACT: Thomas M. Coffman
VA Medical Center, Durham, North Carolina, USA
Phone: (919) 286-6947; Fax: (919) 286-6879; Email: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=28312
Why girls will be girls: molecular safeguards for female sexual development
In the first trimester of human fetal development, the male and female external genitalia are identical. However, although boy and girl babies begin their development as girls, male genital development will occur if high levels of the male steroid hormone testosterone are present at 7–12 weeks, which occurs in female fetuses deficient in an enzyme called CYP21, involved in the production of cortisol. This increase in cortisol is the direct result of a related defect called congenital adrenal hyperplasia, essentially an enlargement of the adrenal glands above the kidneys. Interestingly, if the mother is given a cortisol-like drug called dexamethasone at this point in the pregnancy, the fetal genitalia can be restored back to the female form. Now, in a study appearing in the April issue of the Journal of Clinical Investigation, researcher Neil A. Hanley and colleagues at the Southampton General Hospital in the United Kingdom, report that the reason for this dexamethasone-mediated reversal is due to the drug's suppression of fetal levels of male hormones (adrenal androgens) produced by a critical determinant of gender known as the "hypothalamic-pituitary-adrenal" (HPA) axis. The researchers analyzed adrenal tissue from 121 human fetuses (following ethical approval from their research ethics committee), and found that although the adrenal gland increased in size over the course of 8–10 weeks of development, the content of cortisol dropped by approximately 50%. Further, the authors found that individual adrenal glands from first trimester fetuses were able to produce several different androgens, including testosterone, and that this androgen production was responsive to ACTH (a hormone of the anterior pituitary). Together these data suggest that the adrenal cortex participates in the production of cortisol and androgens during the first trimester of human development, and that adrenocortical activity is correlated to that of the anterior pituitary, and identify an important mechanism for safeguarding female sexual development.
In an accompanying commentary, Perrin C. White from the UT Southwestern Medical Center in Dallas states that "by demonstrating that there is indeed a functioning fetal HPA axis when the external genitalia are differentiating, the present work provides a rationale for prenatal treatment of congenital adrenal hyperplasia due to CYP21 deficiency." In addition, he comments that "this study implies that high doses of dexamethasone are most necessary in the relatively narrow time window when cortisol levels would normally be high and the genitalia are differentiating."
TITLE: In humans, early cortisol biosynthesis provides a mechanism to safeguard sexual development
AUTHOR CONTACT: Neil A. Hanley
Southampton General Hospital, Southampton, United Kingdom
Phone: 44-23-8079-5040; Fax: 44-23-8079-4264; E-mail:N.A.Hanley@soton.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=25091
TITLE: Ontogeny of adrenal steroid biosynthesis: why girls will be girls
AUTHOR CONTACT: Perrin C. White
UT Southwestern Medical Center, Dallas, Texas, USA
Phone: (214) 648-3501; Fax: (214) 648-9772; E-mail: Perrin.firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=28296
Antibodies in arthritis: reacting to self
Rheumatoid arthritis (RA) is a painful inflammatory disorder of the joints. Now, in a study appearing in the April issue of the Journal of Clinical Investigation, researcher V. Michael Holers and colleagues at the University of Colorado Health Sciences Center in Denver examine the pathogenic role of antibodies known as "anti-CCP antibodies," which react against joint proteins that have been "citrullinated" or modified by the addition of a citrulline peptide. The researchers induced arthritis in mice by injecting them with a collagen protein that had been isolated from cows. This procedure resulted not only in the onset of RA in the mice, but also was associated with the production of both anti-collagen and anti-CCP antibodies in the blood. The authors found that sera (blood proteins) from the experimental mouse model of RA and sera from a patient with RA contained antibodies that specifically recognized citrullinated forms of fibrinogen and filaggrin, proteins in the joint tissue. To understand whether these anti-CCP antibodies were a marker of RA, or were involved directly in the destructive process that takes place within the joint during RA disease, the authors delivered to mice antibodies against citrullinated fibrinogen (another protein in the joint), which resulted in an increase in the symptoms of arthritis such as inflammation in the joint, cartilage destruction, bone destruction, as well as changes in the overall appearance of the tissue, including joint swelling. Importantly, animals that were made tolerant (or resistant) to the citrullinated proteins showed a reduced severity of RA. Together, these results demonstrate that antibodies against citrullinated proteins are centrally involved in the pathogenesis of autoimmune rheumatoid arthritis. The authors suggest that future therapeutics which inhibit these antibodies or their development may reduce the severity of disease in patients with active disease, or perhaps even prevent the onset of clinically significant arthritis.
In an accompanying commentary, Cornelia M. Weyand from Emory University School of Medicine in Atlanta states that "the authors deserve praise for these elegant studies, since the study design settles the question of whether anti-CCP antibodies are merely a part of chronic immune stimulation or participate in tissue damage."
TITLE: Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis
AUTHOR CONTACT: V. Michael Holers
University of Colorado Health Sciences Center, Denver, Colorado, USA
Phone: (303) 315-7952; Fax: (303) 315-5540; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=25422
TITLE: Pathomechanisms in rheumatoid arthritis --time for a string theory?
AUTHOR CONTACT: Cornelia M. Weyand
Emory University School of Medicine, Atlanta, Georgia, USA
Phone: (404) 727-7310; Fax: (404) 727-7371; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=28300
Protection from infection: how antioxidant signaling pathways can help
In a study appearing in the April issue of the Journal of Clinical Investigation, researcher Shyam Biswal and colleagues at the Johns Hopkins University in Baltimore report that mice that fail to express Nrf2, a protein involved in the expression of various antioxidant genes, are dramatically more susceptible to death following acute exposure to a bacterial cell wall sugar called LPS and to surgically-induced sepsis. The authors examined post-LPS-treatment lung inflammation in the mice and found that Nrf2-deficient animals had significantly higher levels of inflammatory cells called neutrophils, as well as higher levels of immune cells called macrophages, as soon as 6 hours after LPS exposure. The treatments also stimulated greater development of pulmonary edema, accompanied by elevated blood levels of the early-phase proinflammatory protein TNF-alpha in the Nrf2-deficient mice, compared to normal mice. Examination of antioxidants revealed that Nrf2-deficient mice expressed severely depressed levels of the tissue-protective enzyme glutathione, suggesting that Nrf2 plays a central role in controlling the body's proper immune response during infection. The authors note that these results provide insight into the immune system's response to sepsis and septic shock, and provide avenues for designing novel therapies that could minimize mortality.
In an accompanying commentary, Jay K. Kolls from the Children's Hospital of Pittsburgh in Pennsylvania, puts the work by Biswal and colleagues into the context of a pressing public health need, when he informs us that "despite decades of advances in antibiotic treatment, sepsis remains an elusive killer, with over 750,000 cases per year in North America, with 40-50% mortality in adults." In addition, he notes that these studies "confirm the critical role of the cellular redox state in regulating the immune system and support the contention that antioxidants are critical in regulating the cellular response to external stressors."
TITLE: Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis
AUTHOR CONTACT: Shyam Biswal
Johns Hopkins University, Baltimore, Maryland, USA
Phone: (410) 955-4728; Fax: (410) 955-0116; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=25790
TITLE: Oxidative stress in sepsis: a redox redux
AUTHOR CONTACT: Jay K. Kolls
Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
Phone: (412) 648-7457; Fax: (412) 692-6645; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=28111
Transforming T cells into tumors takes time and tax
Infection with human T cell leukemia virus type 1 (HTLV-1) leads to an aggressive disease called adult T cell leukemia/lymphoma (ATLL) or a related condition called HAM/TSP, following an asymptomatic period of 30 years. HTLV-1 infects blood cells called CD4+ and CD8+ T cells, but only the CD4+ subset becomes leukemic. To better understand why, researchers Eric Wattel and colleagues at the Université Claude Bernard in France isolated T cells from patients with HAM/TSP. The authors found that although both subsets of HTLV-1–infected T cells had higher growth rates than uninfected cells, the mechanisms were different: while CD4+ cells were recruited to enter an active process of cell division called the cell cycle, CD8+ cells were prevented from dying. In addition, although the HTLV-1 viral protein called "tax" was present in both subsets of infected cells, only CD4+ T cells displayed abnormalities in their appearance and defects in a type of cell division called cytokinesis. Thus, the effects of HTLV-1 infection are distinct for each T cell subset. Further study showed that the increased cell cycling (as seen in infected CD4+ cells), but not the reduction in cell death (as seen in infected CD8+ cells), correlated with tax levels, suggesting that tax is a critical determinant of the sensitivity of CD4+ cells to leukemia. The study appears in the April issue of the Journal of Clinical Investigation.
In an accompanying commentary, O. John Semmes from Eastern Virginia Medical School in Norfolk, writes that this study will allow researchers to better identify a postinfection, nonmalignant cell-based on some of the cell's behavior. He further notes that, "the determination of the molecular events that occur between virus infection and disease development has been a particularly challenging area of research."
TITLE: HTLV-1 propels untransformed CD4+ lymphocytes into the cell cycle while protecting CD8+ cells from death
AUTHOR CONTACT: Eric Wattel
Université Claude Bernard, Lyon Cedex, France
Phone: 33-478-78-26-69; Fax: 33-478-78-27-17; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27198
TITLE: Adult T cell leukemia: a tale of 2 T cells
AUTHOR CONTACT: O. John Semmes
Eastern Virginia Medical School, Norfolk, Virginia, USA
Phone: (757) 446-5904; Fax: (757) 446-5766; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=28140
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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