Dr. Xingming Shi, bone biologist at the Medical College of Georgia Institute of Molecular Medicine and Genetics.

Credit: Phil Jones

A small protein may have a big role in helping you make more bone and less fat, researchers say.

"The pathways are parallel, and the idea is if you can somehow disrupt the fat production pathway, you will get more bone," says Dr. Xingming Shi, bone biologist at the Medical College of Georgia Institute of Molecular Medicine and Genetics.

He's found the short-acting protein GILZ appears to make this desirable shift and wants to better understand how it does it with the long-term goal of targeted therapies for osteoporosis, obesity and maybe more.

"Osteoporosis and obesity are two major public health problems, but people have no idea whether they have a connection," says Dr. Shi. Bone and fat do have a common source: both are derived from mesynchymal stem cells. Bone loss and fat gain also tend to happen with age and with use of the powerful, anti-inflammatory steroid hormones glucocorticoids. "When you age, your bone marrow microenvironment changes; the balance between the bone and fat pathway is broken," says Dr. Shi, a faculty member in the MCG Schools of Medicine and Graduate Studies. "You have more fat cells accumulate".

"The bones of elderly people or those who take glucocorticoids are yellow inside instead of red," he says. And it gets worse: in a classic vicious cycle, the more fat, the more cytokines that stimulate production of bone-destroying osteoclasts and inhibit bone-forming osteoblasts. He recently showed that even the stem cells change with age: their numbers and their ability to differentiate decrease.

Weight gain and bone loss are established side effects of glucocorticoids, whose wide-ranging uses include treatment for arthritis, asthma, infections and organ transplants. Ironically, glucocorticoids also induce a short burst of GILZ. GILZ, in turn, inhibits the transcription factor PPAR2, called the master regulator of adipogenesis, or fat production, as well as CCAAT/enhancer-binding proteins that turn on this fat-producing gene. One way GILZ does this is by binding to the regulatory region of PPAR2, Dr. Shi has shown.

To restore a healthier balance of bone and fat production, sustained GILZ action is needed. "When you permanently express GILZ, cells cannot differentiate into fat cells. Instead, you increase bone formation. People like this idea," says Dr. Shi, who has watched the mesynchymal stem cell production shift.

One point of controversy is that, at least in the lab, glucocorticoids seem to enhance bone formation. But Dr. Shi believes it's the short burst of GILZ at work there. He wants to know exactly how it works to see if it could offer a targeted therapy for osteoporosis and obesity and maybe a safer option for many who need glucocorticoids.

A recent $1.5 million, five-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases is enabling Dr. Shi to further test his hypothesis about how GILZ represses PPAR2 and to see if GILZ over-expression in mice reduces PPAR2 expression and consequently increases bone and decreases fat. A long-term goal is to understand exactly how PPAR2 controls fat and bone production.

GILZ also is a powerful immune and inflammation suppressor. It inhibits two key inflammatory molecules, NF-kB and AP-1, which turn on inflammatory genes in response to cytokines, such as TNF- and IL-1, involved in rheumatoid arthritis and other inflammatory diseases, Dr. Shi showed in research published on the cover of the April 15 issue of Journal of Cellular Biochemistry That study notes GILZ's potential as a novel anti-inflammatory therapy.

In fact, Dr. Shi believes GILZ is a key factor mediating the anti-inflammatory effects of glucocorticoids. A long-acting version of GILZ or a similar substance would be needed to produce, for example, a powerful new arthritis treatment minus the undesirable effects. About 50 percent of arthritis patients who take glucocorticoids develop osteoporosis, he notes, worsening an already difficulty condition worse.

People can't take GILZ now, but another long-term goal is to develop a GILZ-like pill that would dramatically reduce fat production. Dr. Shi already has developed a cell line that continuously expresses GILZ.


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HOUSTON -- (July 27, 2008) -- Turning on certain protein receptors in the body has been found to induce preeclampsia, believed to be a pregnancy-induced autoimmune disease, in mouse models, say researchers at Baylor College of Medicine in Houston.

The findings, a collaboration of The University of Texas Health Science Center at Houston, Texas Children's Hospital, and BCM, appear in the current issue of Nature Medicine.

Group of symptoms

"The exact processes that cause preeclampsia in woman aren't known," said Dr. Hong (Amy) Zhang, assistant professor of pathology at BCM. "The disorder manifests through a group of symptoms, most commonly high blood pressure and an abnormal amount of protein in urine."

Preeclampsia is found in about 5 percent of pregnancies, usually starting early in the third trimester. It can cause hypertension, renal functional defect, placental defects, or even death. Currently there is no single reliable screening test and no well established prevention method.

Triggers

"Understanding what triggers it is important to potentially creating a treatment," Zhang added.

It was already known that women suffering from preeclampsia have a higher level of circulating autoantibody (AT1-AA) that binds and activates the angiotensin II receptor type 1a, or AT1 receptor.

Dr. Yang Xia, assistant professor of biochemistry and molecular biology at UTHSC Houston, and his research colleagues were able to isolate a group of antibodies known as immunoglobulin or IgG. From that they were able to extract and purify AT1-AA. Pregnant mice were then injected with either the IgG or AT1-AA.

"Similar symptoms and pathological changes of preeclampsia found in women, such as hypertension and renal damage, were found in the mice," Zhang said.

To make sure that AT1-AA was the protein inducing the symptoms of preeclampsia, researchers co-injected losartan, an AT1 receptor antagonist or a 7 amino acid epitope peptide corresponding to the second extracellular loop of AT1 receptor with the AT1-AA to the pregnant mice. Examining the mice after the co-injection, it was found that the symptoms of preeclampsia were prevented.

"While losartan worked in this mouse model, it is still too early to use as a treatment for preeclampsia. It is harmful to the baby," Zhang said. "However, 7 amino acid epitope peptide may be a specific effective novel therapeutic possibility by targeting on AT1-AA in the disease. This is the first step to finding out what will work."

Zhang added, "our hopes are to continue on this line of research to one day be able to screen for the disorder, or screen for indications that one person might be more susceptible to preeclampsia."

This work is funded by grants from the United States National Institutes of Health, the March of Dimes, and the Texas Higher Education Coordinating Board. The use of losartan was possible through a gift from Merck.

The paper can be found at http://www.nature.com/nm/.

For more research from Baylor College of Medicine in Houston, go to www.bcm.edu/fromthelab or www.bcm.edu/findings.

HOUSTON -- (July 25, 2008) -- Parents are readying their back-to school shopping lists, but there's a lot more to think about than just supplies. Baylor College of Medicine experts touch on topics that range from when to buy adolescents a cell phone to spotting language delays that could impact academic peformance.

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HOUSTON -- (July 24, 2008) -- Parents are starting to make out their back-to-school shopping lists, and along with the usual notebooks, backpacks, pens and pencils, they may find their children urging them to add another item – a cell phone.

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Before letting their kids enter the electronic age of cell phones, music players and personal computers, parents must first make sure they are ready to handle the responsibility, says a Baylor College of Medicine expert in adolescent behavior.

Advantages

"Most kids are about 11 or 12 when they get a cell phone," said Dr. John Sargent, professor of psychiatry and behavioral sciences at BCM, "but even more important than their age is their level of responsibility."

For those adolescents who are ready for a phone, there are many advantages, Sargent noted. Parents are able to keep tabs on their children, plus youngsters can learn important lessons about handling responsibility and setting limits.

Setting limits

But there are a few things parents should keep in mind before buying that new cell phone.

Parents must set guidelines and limits on cell phone use. "No matter what age your child is, if they're in your home, there needs to be supervision."

This includes establishing how many minutes a month your child is allowed to talk on the phone – which can be monitored easily by parents – and how late they are allowed to talk.

Nighttime vigil

Sargent noted that nighttime is when a lot of problems can occur with electronics – like arguing with friends over the phone, staying on the phone too long, visiting inappropriate web sites or staying up too late playing games.

"Parents should be especially aware of what's going on at night," he said. "What you really want is for your child to start to wind down, and if the opposite is happening, it can lead to sleep problems that are disruptive to their education."

Consequences

If those limits are abused, then there needs to be consequences, Sargent urged.

"Children need to understand that they are not entitled to a cell phone or any other electronic device. These are privileges, and they can be removed if they are misused."

If this occurs, parents should take the cell phone away for a short period of time. However, if parents determine that their child just isn't ready for the responsibility, they should take the cell phone away for a longer period of time.

Parents should also require that their child contribute to the cost of a cell phone, even if it's only a minimal amount, Sargent said. Kids will take more responsibility for their phone if they are helping to pay for it.

HOUSTON -- (July 24, 2008) -- Language and literacy go hand in hand.

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Address reading and speaking concerns early to prevent damage to a child's academic career, say developmental experts at Baylor College of Medicine in Houston.

Drs. Sherry Vinson and Adiana Spinks-Franklin, both assistant professors of pediatrics - developmental pediatrics at BCM, said concerned parents should enroll their infants in an early intervention program if they suspect their child is behind on core developmental milestones such as speech and language.

"Children should meet three key milestones by their first birthday," said Spinks-Franklin. "They should say one recognizable word, walk one step and follow a one-step command with gesture."

Behaviors to Watch

Vinson and Spinks-Franklin outlined alarming behavioral characteristics to watch for in children:

• Not responsive to the parent's command ("sit down").
• Not self-initiating (saying "mama") and not following a one-step command given with a gesture (e.g., handing the parent what the child has in his/her hand when the parent holds out a hand and says a command "give that to me") at one year.
• Not self-initiating conversation, saying approximately 50 words, and spontaneously putting two words together ("go home") plus following two simple commands put together without gesture ("touch your nose then clap your hands") at two years.
• Following directions appropriately at one and two years, but not self-initiating the words.

There are significant challenges children with language and speech delays will have later in life if parents do not address the situation, they say. "Language allows them to become strong in so many important areas including academics, reading and social skills," said Spinks-Franklin. "Children with well-developed language skills are overall more productive and perform much better in school."

Reading, they say, can be a huge hurdle for these children but it is crucial for them to master. "If you cannot talk, then you cannot read," said Spinks-Franklin. "These children will have significant reading disorders that will damage their academic career if they are not appropriately addressed at an early age."

Early Intervention

Many states have resourceful, funded programs that evaluate a child's strengths and weaknesses and devise a plan for enhancing their skills.

Vinson and Spinks-Franklin, who are also pediatricians at the Meyer Center for Developmental Pediatrics at Texas Children's Hospital, refer parents to early childhood education programs available to children from birth to three years-old. The programs help children improve all developmental skills in a natural setting. Kids work with a variety of specialists including, speech pathologists, physical and occupational therapists and social workers and also provide psychological, educational and family support.

"The earlier the parents contact a program, the earlier the child can receive services," said Spinks-Franklin. She also added that children do not have to be referred by a doctor to qualify for the services. "Concerned parents should call to have their children evaluated by an educational program."

Clear Benefits

The benefits from evaluation programs are clear, say researchers who have followed the program for years. "Children with developmental delays who are enrolled in an evaluation program perform much better in school than those who are not," said Spinks-Franklin. "We continue to follow them through elementary school, and they continue to do well when compared to children with developmental delays who do not receive early intervention services."

Children involved in early intervention programs are more likely to live independently and graduate from high school, said Spinks-Franklin.

Risk Factors

A variety of factors may cause a child's developmental delay, including genetics, prenatal environment (exposure to tobacco, alcohol or drugs) and premature birth (neurological development occurring outside the womb), they say.

The time it takes to overcome delays depends on the severity of the case. "If a child is challenged in several areas--language, speech, social and motor skills--it is going to take longer to develop language skills than for a child simply dealing with a speech delay," said Spinks-Franklin.

Parental Participation

Most significant is parental participation. "Most programs make house calls only once or twice a week," said Spinks-Franklin. "It is the parent's duty to continue working with their children the rest of the time."

Spinks-Franklin said parents should actively label their child's environment by pointing out objects and colors to help develop certain areas of the brain. Another vital exercise for parents is reading to your child, Spinks-Franklin said.

Children over the age of three can be placed in preschool programs before kindergarten and if they continue to need services after preschool, they should receive special education services from the school system. Private speech and language disabilities programs are also available, including a variety of programs from Texas Children's.

"Early intervention is very beneficial for these children's overall development and quality of life," said Spinks-Franklin. "The involvement and commitment from the parents makes this happen."