骨鈣素在糖代謝中的研究進(jìn)展

楊焱平，封啟明

(上海交通大學(xué)附屬第六人民醫(yī)院急診醫(yī)學(xué)科，上海 200233)

骨鈣素在糖代謝中的研究進(jìn)展

楊焱平，封啟明

(上海交通大學(xué)附屬第六人民醫(yī)院急診醫(yī)學(xué)科，上海 200233)

骨鈣素（Osteocalcin，OC）是成骨細(xì)胞分泌并沉積在骨基質(zhì)中的非膠原蛋白，參與骨的礦化。糖代謝可以影響成骨細(xì)胞活性，最近研究發(fā)現(xiàn)羧化不全骨鈣素(uncarboxylatedostecalcin，ucOC）可以促進(jìn)小鼠胰島β細(xì)胞增殖，胰島素分泌，增強(qiáng)胰島素敏感性，進(jìn)而調(diào)控血糖。在糖尿病人群中也發(fā)現(xiàn)骨鈣素含量與血糖、胰島素抵抗等存在相關(guān)性，這將有助于在控制血糖領(lǐng)域的研究。

骨鈣素；血糖；胰島素；胰島素受體

一直以來，骨骼僅僅被認(rèn)為是構(gòu)成機(jī)體的結(jié)構(gòu)器官，但近年來人們發(fā)現(xiàn)骨骼也是一種內(nèi)分泌器官。通過對小鼠的研究顯示小鼠體內(nèi)成骨細(xì)胞分泌的骨鈣素增加可以調(diào)節(jié)脂肪含量、促進(jìn)胰島β細(xì)胞增殖、增加胰島素的表達(dá)及分泌，降低血糖和改善糖耐量，進(jìn)而調(diào)控機(jī)體能量代謝[1]。骨鈣素作為一種由內(nèi)分泌激素影響糖代謝越來越受到關(guān)注，本文主要闡述關(guān)于骨鈣素對糖代謝影響的研究進(jìn)展。

1 OC的基本情況

OC是一種沉積于骨基質(zhì)中的非膠原蛋白，由成骨細(xì)胞、成牙質(zhì)細(xì)胞、軟骨細(xì)胞分泌，最近研究發(fā)現(xiàn)循環(huán)內(nèi)皮祖細(xì)胞(circulating endothelial progenitor cells，EPCs)中亦可檢測到骨鈣素的存在[2]。骨鈣素基因包含4個外顯子和3個內(nèi)含子，轉(zhuǎn)錄和翻譯過程受維生素D3和維生素K2的影響[3]，翻譯形成的前體骨鈣素含98個氨基酸，該肽鏈在內(nèi)質(zhì)網(wǎng)轉(zhuǎn)移的過程中經(jīng)過兩次裂解，形成含49個氨基酸，分子量約為5 800。絕大多數(shù)骨鈣素[4]在受體樣跨膜蛋白酪氨酸磷酸酶(osteoblast protein tyrosine phosphatase，OST-PTP)和維生素K依賴的γ-谷氨酸羧化酶(γ-glutamylcarboxylase，GGCX)的作用下形成肽鏈中17、21和24號位含γ-羧基谷氨酸殘基的羧化骨鈣素(carboxylated ostecalcin，cOC)[5]。cOC與鈣離子親和力高，有利于結(jié)合羥磷灰石沉積于骨基質(zhì)中[6]，小部分骨鈣素以羧化不全骨鈣素(uncarboxylatedostecalcin，ucOC)的形式釋放入血[3]。血漿中總OC含量依賴于成骨細(xì)胞功能，而ucOC含量依賴維生素K活性[7]。目前已經(jīng)證實(shí)ucOC為骨鈣素的活性形式參與能量的調(diào)節(jié)[1]。

2 OC在糖代謝中的研究進(jìn)展

2.1 胰島素-骨鈣素信號前饋調(diào)節(jié)的形成 胰島素可以通過成骨細(xì)胞膜上的胰島素受體(insulin receptor，Insr)促進(jìn)成骨細(xì)胞增殖和分化，增加骨鈣素mRNA的表達(dá)和OC的分泌[8]，而血清ucOC通過作用于胰島β細(xì)胞膜上的G蛋白耦聯(lián)受體C家族6組(G-protein-coupled receptor 6a，Gprc6a)使小鼠胰島β細(xì)胞增殖、胰島素表達(dá)及分泌增加[1]，該過程為胰島素-骨鈣素信號前饋調(diào)節(jié)[3]。

2.1.1 增強(qiáng)胰島素-骨鈣素信號前饋調(diào)節(jié)的途徑胰島素不僅有促進(jìn)成骨細(xì)胞分化的作用[8-9]，也可通過成骨細(xì)胞膜Insr減弱TWIST2對RUNX2的抑制作用，使鏈接到骨鈣素啟動子的RUNX2比例增加，增強(qiáng)骨鈣素啟動子的表達(dá)[8-10]；同時能使骨保護(hù)素(osteoprotegerin，OPG)的減少表達(dá)[8]，減弱OPG對核因子κB受體活化因子配體(receptor activator for nuclear factor-κB ligand，RANKL)的抑制，進(jìn)而增加破骨細(xì)胞的活性，促使骨基質(zhì)形成pH 4.5的微環(huán)境，該酸性環(huán)境中骨基質(zhì)cOC第C17脫羧，形成ucOC進(jìn)入血液[11]。以上多種途徑共同使血清ucOC濃度增加，增加的ucOC不僅可以直接作用于胰島細(xì)胞膜表面的Gprc6a，也可通過刺激腸細(xì)胞的Gprc6a使腸細(xì)胞分泌人胰高血糖素樣肽1 (glucagon-like peptide-1，GLP-1)增加[12-13]，間接促進(jìn)胰島素分泌增多；另外，血清ucOC不僅可以保護(hù)高血糖環(huán)境下小鼠胰島細(xì)胞的功能[14]，也可以刺激脂肪細(xì)胞分泌脂聯(lián)素進(jìn)而增強(qiáng)胰島素的敏感性[1]。

2.1.2 減弱胰島素-骨鈣素信號前饋調(diào)節(jié)的途徑 研究發(fā)現(xiàn)Esp基因敲除的小鼠血清ucOC水平升高，表明Esp基因介導(dǎo)OC的生成[1]。Esp基因在小鼠成骨細(xì)胞中特異性表達(dá)生成OST-PTP，在GGCX的協(xié)同作用下可以使ucOC羧化成cOC；ESP的活性受轉(zhuǎn)錄激活因子-4(activating transcription factor 4，ATF4)和FoxO1的調(diào)節(jié)，ATF4或FOXO1可與ESP啟動子相連，促進(jìn)下游ESP表達(dá)OST-PTP[15-17]，同時OST-PTP可以抑制Insr的活性[11]，阻礙ucOC的生成。除此之外，持續(xù)高血糖不僅可降低成骨細(xì)胞Insr對胰島素的敏感性，產(chǎn)生胰島素抵抗，也可直接抑制成骨細(xì)胞生長和骨鈣素表達(dá)的作用[18]，Hamada等[19]還發(fā)現(xiàn)高血糖對成骨細(xì)胞有直接的毒害作用，這可能與高血糖刺激活性氧簇(reactive oxygen species，ROS)增多、削弱成骨細(xì)胞功能有關(guān)[20]。

2.2 OC與糖代謝的關(guān)系 Lee等[1]發(fā)現(xiàn)OC缺失小鼠表現(xiàn)出胰島體積和胰島β細(xì)胞數(shù)目下降，血漿中胰島素濃度及胰島素敏感性降低，而血糖濃度升高，出現(xiàn)胰島素抵抗，而外源性O(shè)C能改善該現(xiàn)象，這暗示OC與糖代謝可能呈負(fù)相關(guān)關(guān)系。臨床研究發(fā)現(xiàn)糖尿病患者血清OC呈低水平，同時大部分橫斷面研究均顯示血清骨鈣素與糖代謝指標(biāo)存在負(fù)相關(guān)關(guān)系，即血清骨鈣素水平越低，血糖越高，這種負(fù)相關(guān)關(guān)系同樣存在于血清骨鈣素水平與糖化血紅蛋白及胰島素抵抗指數(shù)之間[21-25]。血清骨鈣素水平越高，穩(wěn)態(tài)模型評估的胰島β細(xì)胞功能越好，這種相關(guān)關(guān)系同樣存在于不同糖耐量狀態(tài)及不同性別的人群中[26-28]。骨鈣素與上述指標(biāo)的負(fù)相關(guān)關(guān)系在糖耐量正常人群、Ⅰ型糖尿病及Ⅱ型糖尿病患者中均存在[29-31]。而且在不同性別、年齡、體重指數(shù)、種族以及是否絕經(jīng)等狀態(tài)下，骨鈣素與糖代謝指標(biāo)之間的變化趨勢似乎都不受影響[32]。

3 展望

動物實(shí)驗(yàn)表明不同濃度的外源性ucOC能調(diào)節(jié)血糖代謝[1]，口服骨鈣素能通過GLP-1途徑促進(jìn)胰島素分泌，胰島細(xì)胞增殖，降低血糖等[13]。骨鈣素對機(jī)體能量代謝平衡起著重要的調(diào)控作用。在人群中對包括骨鈣素在內(nèi)的骨轉(zhuǎn)換血清指標(biāo)及其功能的進(jìn)一步研究，有可能為糖尿病的發(fā)生發(fā)展及治療提供新的理論依據(jù)和思路。近些年的研究多集中于骨鈣素與胰島β細(xì)胞的信號交流，ucOC的受體Gprc6a在胰島素靶組織如骨骼肌、肝臟、脂肪組織內(nèi)都有分布，關(guān)于其作用機(jī)制的研究目前很少，而且人的內(nèi)分泌系統(tǒng)錯綜復(fù)雜，骨、胰島、胰島素靶器官等之間的各種信號通路、各種因素互相影響，難以確定骨鈣素在機(jī)體中調(diào)節(jié)糖代謝和能量代謝中的獨(dú)立性作用，因此，也應(yīng)結(jié)合大量臨床、流行病學(xué)證據(jù)進(jìn)行綜合評價。同時，骨鈣素能否開辟為降血糖藥物也需要得到進(jìn)一步研究證實(shí)?？梢?，隨著骨鈣素對糖代謝的影響及其機(jī)制進(jìn)一步闡明，將開辟糖尿病預(yù)防和治療全新的領(lǐng)域。

[1]Lee NK,Sowa H,Hinoi E,et al.Endocrine regulation of energy metabolism by the skeleton[J].Cell,2007,130(3):456-469.

[2]Mario G,Ulrike IM,Elizabeth JA,et al.Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis[J].Journal of the American College of Cardiology, 2008,52(16):1314-1325.

[3]Shao J,Wang Z,Tieyi Y,et al.Bone regulates glucose metabolism as an endocrine organ through osteocalcin[J].Int J Endocrinol,2015, 2015:967673.

[4]Berkner KL.Vitamin K-dependent carboxylation[J].Vitamins and Hormones,2008,78:131-156.

[5]Lee NK,Karsenty C.Reciprocal regulation of bone and energy metabolism[J].Trends Endocrinol Metab,2008,19(5):161-166.

[6]Collins NC,Thordal-Christensen H,Lipka V,et al.SNARE-protein-mediated disease resistance at the plant cell wall[J].Nature, 2003,425(6961):973-977.

[7]Booth SL,Amanda C,Smith SR,et al.The role of osteocalcin in human glucose metabolism:marker or mediator?[J].Nat Rev Endocrinol,2013,9(1):43-55.

[8]Fulzele K,Riddle RC,Di Girolamo DJ,et al.Insulin receptorsignaling in osteoblasts regulates postnatal bone acquisition and body composition[J].Cell,2010,142(2):309-319.

[9]Fulzele K,DiGirolamo DJ,Liu Z,et al.Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action[J].J Biol Chem,2007,282(35):25649-25658.

[10]Bialek P,Kern B,Yang X,et al.Atwist code determines the onset of osteoblast differentiation[J].Dev Cell,2004,6(3):423-435.

[11]Mathieu F,Jianwen W,Tatsuya Y,et al.Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism[J].Cell, 2010,142(2):296-308.

[12]Mizokami A,Yasutake Y,Gao J,et al.Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice[J].PLoS One,2013,8(2):e57375.

[13]Mizokami A,Yasutake Y,Higashiet S,et al.Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion[J].Bone,2014,69:68-79.

[14]Kover K,Yun Y,Pei YT,et al.Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions[J].Biochem Biophys Res Commun,2015,462(1):21-26.

[15]Wang WG,Lian N,Li LZ,et al.Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription[J].Development,2009,136(24):4143-4153.

[16]Yoshizawa T,Hinoi E,Jung DY,et al.The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts[J].J Clin Invest,2009,119(9):2807-2817.

[17]Rached MT,Kode A,Silva BC,et al.FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of ostecalcin in mice[J].Journal of Clinical Investigation,2010,120(1):357-368.

[18]Wang WW,Zhang XL,Zheng JQ,et al.High glucose stimulates adipogenic and inhibits osteogenic differentiation in MG-63 cells through cAMP/protein kinase A/extracellular signal-regulated kinase pathway[J].Mol Cell Biochem,2010,338(1-2):115-122.

[19]Hamada Y,Fujii H,Fukagawa M.Role of oxidative stress in diabetic bone disorder.Bone[J].2009,45 Suppl 1:35-38.

[20]Mc Cabe LR.Understanding the pathology and mechanisms of type I diabetic bone loss[J].J Cell Biochem,2007,102(6):1343-1357.

[21]Ding HF,Rong HX,Ji H,et al.Change of serum osteocalcin level in type 2 diabetes mellitus patients and its influencing factors[J].Chinese Journal of Osteoporosis,2008,14(7):471-473.

[22]Kindblom JM,Ohlsson C,Ljunggren O,et al.Plasma osteocalcin is inversely related to fat mass and plasma glu-cose in elderly Swedish men[J].J Bone Miner Res,2009,24(5):785-791.

[23]Kanazawa I,Yamaguchi T,Yamauchi M,et al.Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus[J].Osteoporos Int,2011,22 (1):187-194.

[24]Iki M,Tamaki J,Fujita Y,et al.Serum undercarboxylated osteocalcin levels are inversely associated with glycemicstatus and insulin resistance in an elderly Japanese malepopulation:Fujiwara-kyo Osteoporosis Risk in Men(FORMEN)Study[J].Osteoporos Int,2012,23 (2):761-770.

[25]Im JA,Yu BP,Jeon JY,et al.Relationship between osteocalcin and glucose metabolism in postmenopausal women[J].Clin Chim Acta, 2008,396(1-2):66-69.

[26]Zhou M,Ma X,Li H,et al.Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals[J].Eur J Endocrinol,2009,161(5):723-729.

[27]Bao YQ,Zhou M,Zhou J,et al.Relationship between serum osteocalcin and glycaemic variability in type 2 diabetes[J].Clin Exp Pharmacol Physiol,2011,38(1):50-54.

[28]Bao Y,Zhou M,Lu Z,et al.Serum levels of osteocalcin are inversely associated with the metabolic syndrome and the severity of coronary artery disease in Chinese men[J].Clin Endocrinol(Oxf),2011,75 (2):196-201.

[29]Weiler HA,Lowe J,Krahn J,et al.Osteocalcin and vitamin D status are inversely associated with homeostatic model assessment of insulin resistance in Canadian Aboriginal and white women:the First Nations Bone HealthStudy[J].J Nutr Biochem,2013,24(2):412-418.

[30]Choudhury AB,Sarkar PD,Sakalley DK,et al.Role of adiponectin in mediating the association of osteocalcin with insulin resistance and type 2 diabetes:a cross sectionalstudy in pre-and post-menopausal women[J].Archives of Physiology And Biochemistry,2014,120 (2):73-79.

[31]Maddaloni E,D'Onofrio L,Lauria A,et al.Osteocalcinlevels are inversely associated with Hba1c and BMI in adult subjects with long-standing type 1 diabetes[J].J Endocrinol Invest,2014,37(7): 661-666.

[32]Kim SH,Lee JW,Im JA,et al.Serum osteocalcin is related to abdominal obesity in Korean obese and overweight men[J].Clin Chim Acta,2010,411(23-24):2054-2057.

Research progress of osteocalcin in glucose metabolism.

YANG Yan-ping,FENG Qi-ming.Department of Emergency Medicine,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200233,CHINA

Osteocalcin(OC),secreted by osteoblasts,is a non-collagen protein and deposits in bone matrix,affecting bone mineralization.Glucose metabolism can affect osteoblast function.Recent studies have shown that uncarboxylatedostecalcin(ucOC)can promote mouse islet beta cells proliferation and insulin secretion,increase insulin sensitivity and control blood glucose.The findings of the correlations between osteocalcin content and glucose,insulin resistance in patients with type 2 diabetes mellitus(T2DM)would contribute to the control of blood glucose.

Osteocalcin;Blood glucose;Insulin;Insulin receptor

R589.1

A

1003—6350（2016）19—3204—03

10.3969/j.issn.1003-6350.2016.19.036

2015-11-13)

封啟明。E-mail：fengqiming04@126.com