JCI online early table of contents: March 2, 2009

EDITOR'S PICK: Male mice lacking the protein PICK1 mimic one cause of infertility in men Globozoospermia is a rare but severe male infertility disorder. Jun Xia and colleagues, at The Hong Kong University of Science and Technology, People's Republic of China, have now discovered that male mice lacking the protein PICK1 are infertile and that their condition resembles men with globozoospermia, potentially shedding light on this human disorder.

In the study, male mice were found to have a low sperm count, with the remaining sperm looking abnormal (they had round heads) and being severely impaired in their ability to move. Further analysis revealed that compartments in the sperm known as acrosomes, which contain proteins that breakdown the outer membrane of the egg so that a sperm can enter for fertilization to occur, were malformed. As PICK1 was shown to interact with two proteins (GOPC and CK2-alpha') in the vicinity of cellular structures that form acrosomes, the authors suggest that PICK1 has an essential role in acrosome formation.

TITLE: PICK1 deficiency causes male infertility in mice by disrupting acrosome formation

AUTHOR CONTACT:
Jun Xia
The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China.
Phone: (852) 2358-8714; Fax: (852) 2358-1552; E-mail: jxia@ust.hk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36230

EDITOR'S PICK: Getting down to specifics: inhibiting one RANK function prevents bone loss

Soo Young Lee and colleagues, at Ewha Womans University, Republic of Korea, have developed a cell-permeable inhibitor of the mouse protein RANK (which they termed RRI) that is likely to aid in the development of selective drugs to treat diseases that involve substantial bone loss, for example, osteoporosis, periodontitis, and arthritis.

Central to understanding diseases that involve substantial loss of bone density, and thereby loss of bone strength, is insight into the molecules that regulate the formation and function of the cells that slowly breakdown bone, cells known as osteoclasts. One molecule known to regulate both these processes is RANK, however, its utility as a target for drugs that prevent bone destruction might to be limited, as it is involved in many other biological functions. The authors designed RRI to target a region of RANK that they recently found to be specific for the formation of osteoclasts. RRI was found to inhibit in vitro RANKL-induced formation of mouse osteoclasts and in vitro osteoclast-mediated bone destruction. More importantly, it protected against bone loss in two mouse models of diseases associated with bone destruction, leading to the suggestion similar drugs might be beneficial to individuals with diseases that involve bone destruction, such as osteoporosis.

TITLE: Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice

AUTHOR CONTACT:
Soo Young Lee
College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea.
Phone: 82-2-3277-3770; Fax: 82-2-3277-3760; E-mail: leesy@ewha.ac.kr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36809

PARASITOLOGY: Finding a role for the protein GRAIL in diminishing Th2 immune responsiveness

Parasites known as helminths, for example the parasite that causes schistosomiasis (Schistosoma mansoni), often cause chronic infections. Although strong immune responses known as Th2 immune responses are mounted soon after infection, these are insufficient to eradicate the parasite. The strength of the Th2 immune response declines over time, minimizing unwanted damage to the tissues that would result from a persistent strong Th2 immune response. Edward Pearce and colleagues, at the University of Pennsylvania, Philadelphia, have now determined the molecular basis for this decline in the Th2 immune response in a mouse model of chronic schistosomiasis. Specifically, they found that the decline in the Th2 response was the result of Th2 cells upregulating expression of the protein GRAIL, which causes the cells to be hyporesponsive. The authors suggest that these data and future follow-up studies are of relevance to the development of therapies for diseases caused by out of control Th2 responses, such as allergy, asthma, and ulcerative colitis.

TITLE: Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression

AUTHOR CONTACT:
Edward J. Pearce
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-3493; Fax: (215) 746-2295; E-mail: ejpearce@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36534

HEMATOLOGY: Movers and shakers: defining what stops the protein DAF in its tracks

Sequential activation of a series of blood proteins known as complement components occurs when the initial component becomes activated on the surface of cells and/or bacteria and results in cell and/or bacterial death. Healthy cells therefore express cell surface proteins to prevent this happening, for example the protein DAF inhibits activation of complement component 3 (C3). An important property of DAF is its ability to move laterally in the cell membrane so that it can find C3 molecules anywhere on the cell surface. David Golan and colleagues, at Harvard Medical School, Boston, have now tracked individual DAF molecules moving laterally in the membrane of intact human red blood cells and analyzed the molecular interactions that make them stop moving. In the absence of C3, DAF molecules moved freely. However, when a product of C3 cleavage (C3b) was deposited on the surface of the intact human red blood cells, the mobility of these molecules became constrained, because they joined a molecular complex at the cell surface that also contained C3b, GPA, and band 3. Further, this complex was tethered to scaffolding proteins inside the cell. The authors speculate that this complex might be important for the removal of aging red blood cells.

TITLE: C3b deposition on human erythrocytes induces the formation of a membrane skeleton–linked protein complex

AUTHOR CONTACT:
David E. Golan
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 432-2256; Fax: (617) 432-3833; E-mail: dgolan@hms.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36088

Source: Journal of Clinical Investigation