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【medical-news】消化道中的化合物可能与骨形成有关联?

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Chemical in Gut Linked to Bone Formation

Bone formation appears to be controlled by serotonin, a chemical that had been known mainly for its entirely separate role in the brain, researchers are reporting.

The discovery could have enormous implications, osteoporosis experts say, because there is an urgent need for osteoporosis treatments that actually build bone.

The disease affects 10 million Americans over age 50. It results in bone loss, and its hallmark is fragile bones that break easily. There are treatments but, with one exception, they slow further bone loss rather than increase bone formation. The exception, parathyroid hormone, is recommended only for short-term use, costs about $6,700 a year and is given by injection.

But in a paper published online Wednesday in Cell, Dr. Gerard Karsenty, chairman of the department of genetics and development at Columbia University’s College of Physicians and Surgeons, reports his discovery of an unexpected system that appears to control bone formation.

At its heart is serotonin made by the gut, not the brain, whose role outside the brain had been a mystery. Ninety-five percent of the body’s serotonin is made by the gut, but gut serotonin cannot enter the brain because it is barred by a membrane, the so-called blood-brain barrier.

Dr. Karsenty reports, though, that gut serotonin can directly control bone formation. It is released into the blood, and the more serotonin that reaches bone, the more bone is lost. Conversely, the less serotonin, the denser and stronger bones become. Dr. Karsenty could even prevent menopause-induced osteoporosis in mice by slowing serotonin production.

Osteoporosis researchers were dumbfounded.

“I am very excited by this paper,” said Dr. J. Christopher Gallagher, an osteoporosis specialist and professor of medicine at Creighton University. “It is a groundbreaking paper. One is completely surprised.”

“I was astonished — my jaw was dropping,” said Dr. Ronald Margolis, senior adviser for molecular endocrinology at the National Institute of Diabetes and Digestive and Kidney Diseases.

“This is amazing science. Amazing,” said Dr. Clifford J. Rosen, a senior scientist at the Maine Medical Center Research Institute. “The science is spectacular.”

But Dr. Ethel Siris, who directs the Toni Stabile Osteoporosis Center at Columbia, cautioned that the work was not with humans. Instead, it involved mice that were engineered to have human genes.

“This stuff is really exciting basic, underscore basic, research,” she said.

The story of the serotonin-bone connection began with reports of a rare inherited condition causing fragile bones and blindness. Children with the condition had bones so weak they needed wheelchairs or devices to assist them in walking.

The problem turned out to be a mutation that inactivated a gene called LRP5.

A few years later, another mutation was found in LRP5 that produced the opposite effect, extremely dense bones and resistance to osteoporosis. In this case, LRP5 was overactive. People with this gene mutation, Dr. Karsenty said, had jawbones so dense it was difficult to extract their teeth.

Osteoporosis researchers jumped on these findings, realizing LRP5 could hold clues to the disease. But most assumed that LRP5’s role was in bone itself.

With Dr. Karsenty’s work, said Dr. Bjorn R. Olsen, a bone growth researcher at Harvard Medical School, “that has now been proven completely wrong.”

Instead, Dr. Karsenty discovered that LRP5 acts on serotonin-producing cells in the gut. It blocks an enzyme that converts the amino acid tryptophan to serotonin. The more LRP5, the more the enzyme is blocked, and the less serotonin is made. The gene, apparently, has no effect on brain cells that make serotonin.

After the gut releases serotonin into blood, serotonin travels to bone-forming cells and stops them from growing.

“We made mice with the inactivated gene,” Dr. Karsenty said. “The bone-forming cells are on strike.” The cells simply would not grow, and the mice developed severe osteoporosis.

But their bone cells were fine. When Dr. Karsenty grew the cells in the lab, where they were not exposed to serotonin, they grew normally.

That told Dr. Karsenty that the problem was not in the bone cells but in some molecule in the mouse’s circulation. And that, Dr. Karsenty says, led him to serotonin. The mice had four to five times more serotonin in their blood than mice without the mutation.

He tested the idea by adding serotonin to normal mouse bone cells in the laboratory. The cells stopped growing.

He could even control bone formation in the mice with the mutated gene by giving them a diet deficient in tryptophan, the precursor of serotonin. Without much tryptophan, the mice could not make much serotonin. And their bones grew denser. (But animals with a normal version of the gene did not grow denser bones when they ate a tryptophan-deficient diet.)

Dr. Karsenty and his colleagues also did the reverse experiment, making mice with the mutation that causes super-dense bones in humans. Those animals, he said, had “amazing bones” that were hard to break, and they did not develop osteoporosis.

As for patients with the dense bones mutation, they had low levels of serotonin in their blood.

Osteoporosis patients, though, tend to have normal serotonin levels, Dr. Karsenty said. Their disease results not from impaired bone formation but from accelerated bone loss. Bone is constantly being formed and absorbed, but when the balance shifts toward loss more than formation, the result can be osteoporosis. His hope is to find a new drug that depresses the gut’s serotonin synthesis and stimulates bone growth in these patients.

Dr. T. John Martin, an emeritus professor of medicine at the University of Melbourne in Australia, cautions that all this will take years.

He’s enthusiastic, though.

“This will really change thinking in the field,” Dr. Martin said. “It will have a big impact, I’m certain of that.”

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2008-11-27 09:41 浏览 : 1659 回复 : 4

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2008-11-29 13:25

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Chemical in Gut Linked to Bone Formation
消化道中的化学物质与骨形成有关
Bone formation appears to be controlled by serotonin, a chemical that had been known mainly for its entirely separate role in the brain, researchers are reporting.
研究显示，骨形成似乎是受血液中的复合胺控制的，而过去复合胺被认为只作用于大脑。
The discovery could have enormous implications, osteoporosis experts say, because there is an urgent need for osteoporosis treatments that actually build bone.
研究骨质疏松的专家认为，这个发现可能有巨大的价值，因为对于骨质疏松的治疗，造骨的非常迫切的要求
The disease affects 10 million Americans over age 50. It results in bone loss, and its hallmark is fragile bones that break easily. There are treatments but, with one exception, they slow further bone loss rather than increase bone formation. The exception, parathyroid hormone, is recommended only for short-term use, costs about $6,700 a year and is given by injection.
50岁以上的美国人有一千万人患骨质疏松。它会导致骨质流失，骨头脆弱，易发生骨折。治疗措施大多只能减慢骨质的进一步流失，而不是增加造骨。这样，甲状旁腺激素只用于短期治疗就需要每年花费6700美元，并需要注射给药。
But in a paper published online Wednesday in Cell, Dr. Gerard Karsenty, chairman of the department of genetics and development at Columbia University’s College of Physicians and Surgeons, reports his discovery of an unexpected system that appears to control bone formation.
哥伦比亚大学医学院遗传与发展部主席Gerard Karsenty博士在星期四《细胞》杂志上发表的一篇论文中报告了他的发现，一个意想不到的系统似乎控制者骨形成。
At its heart is serotonin made by the gut, not the brain, whose role outside the brain had been a mystery. Ninety-five percent of the body’s serotonin is made by the gut, but gut serotonin cannot enter the brain because it is barred by a membrane, the so-called blood-brain barrier.
发现的核心在于消化道中生成的复合胺，这种复合胺在脑外的作用一直是一个谜。人体内95％的复合胺是由消化道生成的，但消化道复合胺由于血脑屏障的阻隔作用无法到达脑部。
Dr. Karsenty reports, though, that gut serotonin can directly control bone formation. It is released into the blood, and the more serotonin that reaches bone, the more bone is lost. Conversely, the less serotonin, the denser and stronger bones become. Dr. Karsenty could even prevent menopause-induced osteoporosis in mice by slowing serotonin production.
但Karsenty博士认为，消化道复合胺能直接控制骨形成。在消化道中形成的复合胺被释放到血液中，复合胺到达骨头的数量越多，骨头流失得越多。相反，复合胺越少，骨密度越高，骨头越强健。Karsenty博士通过减慢复合胺的生成预防小鼠绝经期骨质疏松。
Osteoporosis researchers were dumbfounded.
骨质疏松研究者被惊呆了。
“I am very excited by this paper,” said Dr. J. Christopher Gallagher, an osteoporosis specialist and professor of medicine at Creighton University. “It is a groundbreaking paper. One is completely surprised.”
“看到这篇论文我很兴奋”骨质疏松专业医生、 Creighton大学内科学教授J. Christopher Gallagher博士说“这是具有里程碑意义的论文，完全出人意料”
“I was astonished — my jaw was dropping,” said Dr. Ronald Margolis, senior adviser for molecular endocrinology at the National Institute of Diabetes and Digestive and Kidney Diseases.
“我惊讶得下巴都要掉下来了”国家糖尿病和消化道疾病及肾病协会的分子内分泌学高级顾问Ronald Margolis博士说
“This is amazing science. Amazing,” said Dr., a senior scientist at the Maine Medical Center Research Institute. “The science is spectacular.”
“这是一个令人惊讶的研究，太令人惊讶了”缅因州内科中心研究所的高级科学家Clifford J. Rosen博士说“这项研究很吸引人”
But Dr. Ethel Siris, who directs the Toni Stabile Osteoporosis Center at Columbia, cautioned that the work was not with humans. Instead, it involved mice that were engineered to have human genes.
哥伦比亚Toni Stabile骨质疏松中心主任Ethel Siris博士则警告说，这个研究并不是针对人体的，而是针对警告基因改制的有人类基因的小鼠
“This stuff is really exciting basic, underscore basic, research,” she said.
“这份资料真是令人兴奋基础，只是基础研究”她说道。
The story of the serotonin-bone connection began with reports of a rare inherited condition causing fragile bones and blindness. Children with the condition had bones so weak they needed wheelchairs or devices to assist them in walking.
把复合胺和骨联系起来开始于一种导致骨头易碎和失明的罕见遗传病。得这种病的儿童骨头非常脆弱以至于需要轮椅或其他器械帮助他们行走。
The problem turned out to be a mutation that inactivated a gene called LRP5.
这个问题产生于导致LRP5基因活动受阻的变异。
A few years later, another mutation was found in LRP5 that produced the opposite effect, extremely dense bones and resistance to osteoporosis. In this case, LRP5 was overactive. People with this gene mutation, Dr. Karsenty said, had jawbones so dense it was difficult to extract their teeth.
几年后， LRP5基因的另一个变异被发现能相反的作用，即骨密度异常高和抵抗骨质疏松，在这种情况下，LRP5基因过于活跃。Karsenty博士说：有这种基因变异的人颚骨密度非常高，以至于难以拔牙。
Osteoporosis researchers jumped on these findings, realizing LRP5 could hold clues to the disease. But most assumed that LRP5’s role was in bone itself.
骨质疏松研究者对这些发现做了更深入的研究，明确了LRP5与骨质疏松紧密相关。但大多数假定LRP5的作用在骨头本身。
With Dr. Karsenty’s work, said Dr. Bjorn R. Olsen, a bone growth researcher at Harvard Medical School, “that has now been proven completely wrong.”
由于Karsenty博士的研究哈佛医学院骨生长研究员Bjorn R. Olsen博士说：“过去的假定已经证明是完全错误的。”
Instead, Dr. Karsenty discovered that LRP5 acts on serotonin-producing cells in the gut. It blocks an enzyme that converts the amino acid tryptophan to serotonin. The more LRP5, the more the enzyme is blocked, and the less serotonin is made. The gene, apparently, has no effect on brain cells that make serotonin.
Karsenty博士发现LRP5对消化道复合胺制造细胞起作用。它阻滞把色氨酸转化为复合胺的酶的作用。LRP5越多，越多的酶被阻滞，复合胺产生越少。这个基因，显然对制造复合胺的脑细胞不会有影响。
After the gut releases serotonin into blood, serotonin travels to bone-forming cells and stops them from growing.
消化道释放复合胺到血液中以后，复合胺到达成骨细胞，阻止他们的生长。
“We made mice with the inactivated gene,” Dr. Karsenty said. “The bone-forming cells are on strike.” The cells simply would not grow, and the mice developed severe osteoporosis.
“我们培养了有不活跃基因的小鼠” Karsenty博士说，“成骨细胞***了”细胞只是不生长，小鼠得了严重的骨质疏松。
But their bone cells were fine. When Dr. Karsenty grew the cells in the lab, where they were not exposed to serotonin, they grew normally.
但小鼠骨细胞以前是好的。在Karsenty博士实验室培养细胞没有受到复合胺影响的时候，细胞生长正常。
That told Dr. Karsenty that the problem was not in the bone cells but in some molecule in the mouse’s circulation. And that, Dr. Karsenty says, led him to serotonin. The mice had four to five times more serotonin in their blood than mice without the mutation.
这提示了问题不在于骨细胞，而在于小鼠体内的某种物质。Karsenty博士认为这种物质是复合胺。这些小鼠体内的复合胺水平比没有突变的小鼠高4到5倍。
He tested the idea by adding serotonin to normal mouse bone cells in the laboratory. The cells stopped growing.
他通过增加实验室中普通小鼠的骨细胞复合胺来验证这个结论，这些细胞停止了生长
He could even control bone formation in the mice with the mutated gene by giving them a diet deficient in tryptophan, the precursor of serotonin. Without much tryptophan, the mice could not make much serotonin. And their bones grew denser. (But animals with a normal version of the gene did not grow denser bones when they ate a tryptophan-deficient diet.)
他甚至通过喂给复合胺前体色氨酸缺乏的饲料来控制变异基因鼠的骨形成。没有很多的色氨酸，小鼠就无法制造很多复合胺，他们的骨密度提高了。（但基因正常的动物给予色氨酸缺乏的饲料时骨密度并不提高）
Dr. Karsenty and his colleagues also did the reverse experiment, making mice with the mutation that causes super-dense bones in humans. Those animals, he said, had “amazing bones” that were hard to break, and they did not develop osteoporosis.
Karsenty博士和他的同事也做了相反的试验，培育了高密度骨的小鼠，那些动物，他说，有“令人惊异的骨头”坚硬得难以折断，不会得骨质疏松
As for patients with the dense bones mutation, they had low levels of serotonin in their blood.
至于这些有密集骨头突变的患者，他们血液中复合胺水平很低。
Osteoporosis patients, though, tend to have normal serotonin levels, Dr. Karsenty said. Their disease results not from impaired bone formation but from accelerated bone loss. Bone is constantly being formed and absorbed, but when the balance shifts toward loss more than formation, the result can be osteoporosis. His hope is to find a new drug that depresses the gut’s serotonin synthesis and stimulates bone growth in these patients.
骨质疏松患者复合胺水平趋于正常，Karsenty博士说。患者得骨质疏松不是因为骨形成减慢，而是因为骨质流失加快。骨总是在形成和消减，但当这个平衡倾斜为流失大于形成时，就导致了骨质疏松。他希望能发现一种能减少消化道复合胺合成的新药，以刺激患者的骨生长。
Dr. T. John Martin, an emeritus professor of medicine at the University of Melbourne in Australia, cautions that all this will take years.
澳大利亚墨尔本大学的内科学荣誉教授T. John Martin博士谨慎地认为这将花费好多年。
He’s enthusiastic, though.
但他对此很感兴趣。
“This will really change thinking in the field,” Dr. Martin said. “It will have a big impact, I’m certain of that.”
“这将真正改变这个领域的观点” Martin博士说，“我确信，这方面将有一个大的突破。”

2008-11-30 15:03

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消化道中的化学物质与骨形成有关
研究显示，骨形成似乎是受血液中的复合胺控制的，而过去复合胺被认为只作用于大脑。
研究骨质疏松的专家认为，这个发现可能有巨大的价值，因为对于骨质疏松的治疗，造骨的非常迫切的要求。
50岁以上的美国人有一千万人患骨质疏松。它会导致骨质流失，骨头脆弱，易发生骨折。治疗措施大多只能减慢骨质的进一步流失，而不是增加造骨。这样，甲状旁腺激素只用于短期治疗就需要每年花费6700美元，并需要注射给药。
哥伦比亚大学医学院遗传与发展部主席Gerard Karsenty博士在星期四《细胞》杂志上发表的一篇论文中报告了他的发现，一个意想不到的系统似乎控制者骨形成。
发现的核心在于消化道中生成的复合胺，这种复合胺在脑外的作用一直是一个谜。人体内95％的复合胺是由消化道生成的，但消化道复合胺由于血脑屏障的阻隔作用无法到达脑部。
但Karsenty博士认为，消化道复合胺能直接控制骨形成。在消化道中形成的复合胺被释放到血液中，复合胺到达骨头的数量越多，骨头流失得越多。相反，复合胺越少，骨密度越高，骨头越强健。Karsenty博士通过减慢复合胺的生成预防小鼠绝经期骨质疏松。
骨质疏松研究者被惊呆了。
“看到这篇论文我很兴奋”骨质疏松专业医生、 Creighton大学内科学教授J. Christopher Gallagher博士说“这是具有里程碑意义的论文，完全出人意料”。
“我惊讶得下巴都要掉下来了”国家糖尿病和消化道疾病及肾病协会的分子内分泌学高级顾问Ronald Margolis博士说。
“这是一个令人惊讶的研究，太令人惊讶了”缅因州内科中心研究所的高级科学家Clifford J. Rosen博士说，“这项研究很吸引人。”
哥伦比亚Toni Stabile骨质疏松中心主任Ethel Siris博士则警告说，这个研究并不是针对人体的，而是针对警告基因改制的有人类基因的小鼠。
“这份资料真是令人兴奋基础，只是基础研究”她说道。
把复合胺和骨联系起来开始于一种导致骨头易碎和失明的罕见遗传病。得这种病的儿童骨头非常脆弱以至于需要轮椅或其他器械帮助他们行走。
这个问题产生于导致LRP5基因活动受阻的变异。
几年后， LRP5基因的另一个变异被发现能相反的作用，即骨密度异常高和抵抗骨质疏松，在这种情况下，LRP5基因过于活跃。Karsenty博士说：有这种基因变异的人颚骨密度非常高，以至于难以拔牙。
骨质疏松研究者对这些发现做了更深入的研究，明确了LRP5与骨质疏松紧密相关。但大多数假定LRP5的作用在骨头本身。
由于Karsenty博士的研究哈佛医学院骨生长研究员Bjorn R. Olsen博士说：“过去的假定已经证明是完全错误的。”
Karsenty博士发现LRP5对消化道复合胺制造细胞起作用。它阻滞把色氨酸转化为复合胺的酶的作用。LRP5越多，越多的酶被阻滞，复合胺产生越少。这个基因，显然对制造复合胺的脑细胞不会有影响。
消化道释放复合胺到血液中以后，复合胺到达成骨细胞，阻止他们的生长。
“我们培养了有不活跃基因的小鼠” Karsenty博士说，“成骨细胞***了”细胞只是不生长，小鼠得了严重的骨质疏松。
但小鼠骨细胞以前是好的。在Karsenty博士实验室培养细胞没有受到复合胺影响的时候，细胞生长正常。
这提示了问题不在于骨细胞，而在于小鼠体内的某种物质。Karsenty博士认为这种物质是复合胺。这些小鼠体内的复合胺水平比没有突变的小鼠高4到5倍。
他通过增加实验室中普通小鼠的骨细胞复合胺来验证这个结论，这些细胞停止了生长。
他甚至通过喂给复合胺前体色氨酸缺乏的饲料来控制变异基因鼠的骨形成。没有很多的色氨酸，小鼠就无法制造很多复合胺，他们的骨密度提高了。（但基因正常的动物给予色氨酸缺乏的饲料时骨密度并不提高）。
Karsenty博士和他的同事也做了相反的试验，培育了高密度骨的小鼠，那些动物，他说，有“令人惊异的骨头”坚硬得难以折断，不会得骨质疏松。
至于这些有密集骨头突变的患者，他们血液中复合胺水平很低。
骨质疏松患者复合胺水平趋于正常，Karsenty博士说。患者得骨质疏松不是因为骨形成减慢，而是因为骨质流失加快。骨总是在形成和消减，但当这个平衡倾斜为流失大于形成时，就导致了骨质疏松。他希望能发现一种能减少消化道复合胺合成的新药，以刺激患者的骨生长。
澳大利亚墨尔本大学的内科学荣誉教授T. John Martin博士谨慎地认为这将花费好多年。
但他对此很感兴趣。
“这将真正改变这个领域的观点” Martin博士说，“我确信，这方面将有一个大的突破。”

2008-11-30 15:10

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