사춘기 성장하는 애들의 골대사지표물질-끝

[권강범]

Bone Turnover Markers during Pubertal.pdf

이 abstract에 성장을 접근하는 방식에 대해서 함축적으로 다 이야기를 하고 있는 것 같네요....한번 보까요?

-->사춘기동안 일어나는 skeletal mass의 빠른 증가는 세로로 늘어나고 가로로 두꺼워지는 것 때문이다. 골이 성장하는데 지표물질은 오줌이나 혈액에서 측정할수 있는 조골세포와 파골세포에서 생산되는 물질임. 이러한 지표물질들의 증가는 사춘기때 성장함에따라 증가하고 성인이 돼감에 따라 감소함. 성장의 시작은 성호르몬(androgen, estrogen)의 증가를 수반함. 성호르몬에 의한 골염(bone mineral)의 성장은 주로 성장호르몬(growth hormone)과 인슐린 유사 성장호르몬(insulin like growth factor-1)에 의해 이뤄지기도 하도 또한 직접적인 작용을 하기도 함(뼈는 골기질 (bone matrix)과 골염 (bone mineral)으로 구성되어 있고 그 비율은 일정하며 골기질과 골염을 합쳐 골량 (bone mass)이라고 함). 성장기 골염이 성장하는데 중요한 요소는 최적의 영양상태, 이를 받아들이는 몸의 구성, 운동 형태임. 이러한 요소들은 에너지 균형과 관련이 있으며, 다양한 성장요소와 adipocytokine(지방조직에서 분비되는 내분비 물질)과 같은 말초 지표자들이 골격을 성장시키는데 긍정적인 영향을 미침. 종합해보면 애들이 성장하는 동안 골염의 증가는 운동 패턴, 다양한 몸의 구성, 성장 인자, adipocytokine, 성호르몬들 사이의 복잡한 상호 작용에 의해 이뤄짐.

위의 표는 임상 및 실험에서 사용되는 bone turnover marker들입니다. Bone formation marker는 osteoblast(조골세포) proliferation, differentiation시 증가하는 지표 물질이고 bone resorption marker는 osteoclast(파골세포)가 bone을 파괴하면서 흘러나오는 지표물질입니다. Bone은 조골세포와 파골세포의 균형잡힌 활동(bone turnover)에 의해 형성되는데, 보통 애들의 경우 조골세포의 기능이 파골세포의 기능에 비해 우수하고 나이가 듦에 따라 파골세포의 기능이 조골세포의 기능에 비해 우수합니다. 파골세포가 bone을 파괴해서 칼슘,  인 등과 같은 mineral을 분비시키는 것을 bone resorption이라 하고요...bone resorption의 정의에 대해 Wikipedia에서 떠다 아래에다 옮김니다....한번 읽어 보시고요....

Bone resorption is the process by which osteoclasts break down bone^[1] and release the minerals, resulting in a transfer of calcium from bone fluid to the blood. 

The osteoclasts are multi-nucleated cells that contain numerous mitochondria and lysosomes. These are the cells responsible for the resorption of bone. Osteoclasts are generally present on the outer layer of bone, just beneath the periosteum. Attachment of the osteoclast to the osteon begins the process. The osteoclast then induces an infolding of its cell membrane and secretes collagenase and other enzymes important in the resorption process. High levels of calcium, magnesium, phosphate and products of collagen will be released into the extracellular fluid as the osteoclasts tunnel into the mineralized bone. Osteoclasts are also prominent in the tissue destruction commonly found in psoriatic arthritis and other rheumatology related disorders.

Bone resorption can also be the result of disuse and the lack of stimulus for bone maintenance. Astronauts, for instance will undergo a certain amount of bone resorption due to the lack of gravity, providing the proper stimulus for bone maintenance.

During childhood, bone formation exceeds resorption, but as the aging process occurs, resorption exceeds formation.

<Five Stages of Puberty>

Stage 1

In Tanner Stage 1, the child is pre-pubertal. The levels of reproductive hormones are low, and there are no signs of development of the secondary sex characteristics (breasts for girls, penis growth for boys, and appearance of pubic hair for both). Children are expected to grow about 5cm to 6cm in height per year, below the rate of the growth spurts typical in later stages of puberty. (9-13 age)

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Stage 2

Tanner Stage 2 is the first stage of actual puberty. At this stage, the hormonal axis has matured enough to start causing visible signs of puberty. In girls, breast buds develop. In boys, the scrotum (sac that holds the testes) and testes grow and the scrotum might look red and less smooth. You can expect an increased rate of growth in girls of 7cm to 8 cm per year, while boys continue to grow at the pre-pubertal rate of 5cm to 6cm per year. Sparse and relatively light and straight pubic hairs appear in boys and girls.

Stage 3

Girls' breasts continue to grow, but the areola is still flush with the breast. For boys, the penis starts to grow longer, and the testes keep growing. Boys can expect to grow about 7cm to 8cm taller per year, and girls reach their peak growth rate of about 8cm per year. For both sexes, pubic hair darkens and grows coarser and curlier.

Stage 4

Stage 4 is the final stage of pubertal changes. In girls, the areola of the breast now forms a distinct mound above the breast itself. Boys' penises grow thicker, and the testes and scrotum are larger than in Tanner Stage 3. The skin of the scrotum also gets darker. Boys reach their peak growth in height of about 10cm per year; girls' growth is already slowing to about 7cm per year. Pubic hair looks like adult pubic hair but does not cover as much area.

Stage 5

At Tanner Stage 5, puberty is really over and the former child is now a biological adult. Breasts and penises look fully mature, as does pubic hair. Boys reach their maximum height when they are about 17 and girls stop growing taller around 16.

Typically, concentrations of most bone turnover markers increase from prepuberty to mid-puberty and decline during late puberty with the lowest values in the transition to adulthood [4, 15, 23, 26]. Because growth and puberty are usually completed by late adolescence, markers of bone formation and bone resorption converge into adult values [19].

이건 해석은 필요없을 것 같은 애들 2차 성징이 나타나 진행하는 시기(puberty)에 성장이 이뤄지므로 pubertal stage를 이해할 필요가 있을 것 같아서......위에 나온 age는 모두다 만 나이입니다......

Bone Turnover and Physical Activity

Indeed, female athletes involved in high-impact sports such as basketball and volleyball displayed higher levels of serum 

OC, a bone formation marker, and higher BMDs at weight-bearing sites compared to athletes participating in a nonimpact sport (swimming) and control subjects [16]. In another study, higher levels of serum OC were reported in adolescent athletes compared to adult athletes [34], which is consistent with the increased state of bone turnover in the adolescent years [7].

농구나 배구 같은 high-impact 운동을 하고 있는 여자 선수들이 수영 같은 non-impact 운동을 하고 있는 선수와 비교했을때 골형성 지표물질인 osteocalcin과 bone mineral density가 높았으며, 또 다른 보고에 의하면 청소년기 운동선수가 성인 운동 선수에 비해 혈중osteocalcin 농도가 높았다. 이는 청소년기에 bone turnover가 증가함을 시사한다.

The only longitudinal study with adolescent athletes was undertaken by Eliakim et al. [33]. Thirty-eight healthy males (15–17 years of age) participated in a 5-week programme in which one group of participants was assigned to a training condition

consisting of a 2-hour daily endurance training programme five times a week, and the group represented the control condition without physical activity. Training resulted in an increase in bone formation (OC, BAP, PICP) and a decrease in bone resorption

(NTX) markers.

사춘기 운동을 이용한 장기적인 운동 실험. 38명(15-17세)의 건강한 남자 아니들은 5회/week, 2 hr/day, endurance training(아래 표 참조)은 bone formation marker를 증가 시키고 bone resorption 지표물질을 감소시킴.

Relationship of Growth Factors with Bone Metabolism Values

The initiation of puberty is accompanied by an increase in sex hormones [11, 23]. However, the effects of sex hormones on bone are mediated mainly by GH and IGF-I [36], but they also exert a direct effect on bone metabolism [23, 26, 37]. In early

puberty, bone development is stimulated by low levels of circulating sex hormones in combination with increasing levels of GH and IGF-1 [23]. Both estrogens and androgens have been shown to stimulate the proliferation of osteoblasts [38].

sex hormone(estrogen, androgen), GH, IGF-1: bone development에 중요함....

IGF-1 is an important regulator of bone turnover at the tissue level. It has been shown to enhance osteoblast proliferation, to stimulate type 1 collagen production and to modulate osteoblast-ostoeclast interactions [24]. Most GH anabolic actions

on bone are also mediated through IGF-1 [41]. The role of IGF-1 in bone mineralization is particularly important around the age of 13–14 years when the pubertal growth spurt should reach its peak [37, 42]. The positive associations between IGF-1 and bone turnover markers have been reported during all pubertal stages [23].

굵은 글씨 한번 보시면 IGF-1이 성장호르몬과 더불어 아주 중요하단 애기죠....

IGF-1에 대해 기초 지식을 알아봅시다.....ㅋㅋ in Wikipedia.

Definision

Insulin-like growth factor 1 (IGF-1) also known as somatomedin C ormechano growth factor is a protein that in humans is encoded by the IGF1gene.^[1][2] IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin is used for the treatment of growth failure.^[4]

Synthesis and circulation

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a aracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.

Mechanism of action

Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as ""IGF1R"", present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, initiates intracellular signaling; IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves,skin, hematopoietic cell, and lungs.

Receptors

IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than the IGF-1 that is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia)..

IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Other IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.

As a therapeutic agent

IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to IGFBP-3, IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to IGFBP-3, IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, IGFR, its binding does not interfere with IGF-1 function. For these reasons, an IGF-1/IGFBP-3 combination approach was approved for human treatment... brought forward by a small company called Insmed. However, Insmed fell afoul patent issues, and was ordered to desist in this approach.

Relationships of Adipocytokines with Bone Metabolism Values

뼈의 성장과 지방조직과 지방조직에서 분비하는 adipocytokines에 대한 애기는 대부분 가설단계에 있네요....

--> 이 논문을 읽고 성장에 대한 접근을 어떻게 해야 할지 정리해보면

1. 일단 성장에 있어서 pubertal stage에 대한 이해가 필요하고(2차 성징의 발달 시기와 유사하므로), 그에 따른 sex hormone의 골대사에 대한 역할을 공부해야 함.

2. 뇌하수체 전엽에서 분비되는 성장호르몬과 이에 의해 간에서 분비되는 insulin-like growth factor-1의 osteoblast proliferation and differentiation에 대한 이해가 필요함.

3. Insulin link growth factor-1의 작용을 조절하는 IGFBP에 대한 이해가 필요함......

이상입니다. 

아래 첨부한 논문은 위의 review article에 대한 증거 논문입니다.

같이 읽어보시면 다 이해하실듯 해서 다른 설명은 안하고 논문만 첨부하네요......

Bone metabolism markers and bone mass in healthy pubertal b.pdf

[문형철]

6년전 수련의와 함께 osteoporosis에 대해서 상당한 논문을 읽어서 그때 기억이 나겠다 ㅎㅎㅎ

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