动物营养学报 >

2026 , Vol. 38 >Issue 8: 5629 - 5636

DOI: https://doi.org/10.12418/CJAN2026.451

综述

鹿茸的生物学特性及视黄酸信号通路在鹿茸生长中的调控机制研究进展

  • 刘欢欢 ,
  • 司华哲 ,
  • 李志鹏 ,
  • 南韦肖 , *
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  • 吉林农业大学动物科学技术学院, 长春 130118
*南韦肖,讲师,硕士生导师,E-mail:

刘欢欢(2002—),女,辽宁葫芦岛人,硕士研究生,从事鹿茸间充质干细胞研究。E-mail:

Office editor: 武海龙

收稿日期: 2026-01-08

  网络出版日期: 2026-08-13

基金资助

国家重点研发计划(2023YFD1302000)

吉林省科技发展计划项目(20240101239JC)

吉林省教育厅科学研究项目(JJKH20261452KJ)

收起

Research Progress on Biological Characteristics of Antler and Regulatory Mechanism of Retinoic Acid Signaling Pathway in Antler Growth

  • LIU Huanhuan ,
  • SI Huazhe ,
  • LI Zhipeng ,
  • NAN Weixiao , *
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  • College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
*lecturer, E-mail:

Received date: 2026-01-08

  Online published: 2026-08-13

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摘要

鹿茸是梅花鹿重要的经济性状,其产量和品质直接关系到养殖效益。鹿茸的快速再生和生长主要依赖于生长中心细胞的增殖与分化,其中,鹿茸间充质干细胞(AnSCs)的成软骨分化是影响鹿茸组织形成和生长速度的重要细胞学基础,也是影响鹿茸产量的关键生物学过程。视黄酸(RA)是维生素A的活性代谢产物,RA信号通路在调控AnSCs命运中的作用日益受到关注。本文围绕鹿茸生长过程中相关细胞分化与调控机制,系统梳理了RA信号通路组成和功能,并探讨了其对AnSCs分化及在鹿茸生长过程中的潜在作用,以期为梅花鹿生茸期的维生素A营养调控及提高鹿茸产量提供参考。

关键词： 维生素A; 鹿茸间充质干细胞; 视黄酸信号通路; 成软骨分化; 代谢调控

本文引用格式

刘欢欢 , 司华哲 , 李志鹏 , 南韦肖 . 鹿茸的生物学特性及视黄酸信号通路在鹿茸生长中的调控机制研究进展[J]. 动物营养学报, 2026 , 38(8) : 5629 -5636 . DOI: 10.12418/CJAN2026.451

Abstract

Antler is an important economic trait of sika deer, and its yield and quality are directly related to the economic benefits. The rapid regeneration and growth of antler mainly depend on the proliferation and differentiation of cells in the growth center. Among these processes, the chondrogenic differentiation of antler mesenchymal stem cells (AnSCs) serves as an important cellular basis for antler tissue formation and growth and represents a key biological process affecting antler yield. Retinoic acid (RA) is the active metabolite of vitamin A, RA signaling pathway has attracted increasing attention for its role in regulating the fate of AnSCs. This review focuses on cellular differentiation and regulatory mechanisms involved in antler growth, systematically summarizes the composition and functions of the RA signaling pathway, and discusses its potential roles in AnSC differentiation and antler growth, aiming to provide a reference for vitamin A nutritional regulation in sika deer during the antler growth period and for improving antler yield.

Key words： vitamin A; antler mesenchymal stem cells; retinoic acid signaling pathway; chondrogenic differentiation; metabolic regulation

鹿茸是梅花鹿、马鹿等雄鹿可周期性再生的器官,在保健和疾病治疗方面具有重要应用价值。传统中医认为,鹿茸具有补肾壮阳、强筋壮骨的功效[1]。近期研究表明,鹿茸中富含多种生物活性成分,其功能也极其广泛,如修复骨骼损伤、抗癌、抗氧化、抗炎、治疗神经性疾病等[2-4],具有良好的临床应用前景。因此,提升鹿茸生产效率和产量对养鹿业、中药开发等方面均具有重要意义。鹿茸的快速生长依赖于细胞层面的持续增殖更新与定向分化。鹿茸生长中心(antler growth center,AGC)富集多种鹿茸间充质干细胞(antler mesenchymal stem cells,AnSCs),是驱动鹿茸组织形成和再生的重要细胞基础[5-6]。AGC内细胞具有自我更新和多向分化潜能,可向软骨谱系分化并促进软骨细胞外基质(extracellular matrix,ECM)的合成与沉积;随后软骨组织经历成熟与矿化,并向骨组织转化,从而推动鹿茸组织的生长[7-8]。Ba等[9]分析了生长30 d鹿茸的5个层区的基因表达模式,鉴定出了370个关键基因,包括胶原蛋白Ⅱ型α1链(collagen type Ⅱ alpha 1 chain,COL2A1)、胶原蛋白Ⅹ型α1链(collagen type Ⅹ alpha 1 chain,COL10A1)和SRY-box转录因子9(SRY-box transcription factor 9,SOX9)等成软骨标志基因以及胰岛素样生长因子-1受体(insulin-like growth factor-1 receptor,IGF1R)、成纤维细胞生长因子受体3(fibroblast growth factor receptor 3,FGFR3)和转化生长因子-β1(transforming growth factor-β1,TGF-β1)等生长因子受体基因,主要参与了AnSCs增殖分化与软骨形成,进而从分子层面证明了AnSCs成软骨分化在鹿茸生长过程中的重要性。综上所述,鹿茸AnSCs成软骨分化是鹿茸生长的关键环节。
维生素A(vitamin A,VA)是动物必需的脂溶性维生素,在维持动物正常生长发育、促进蛋白质的合成、维持骨骼生长发育以及骨细胞的分化等方面发挥重要作用[10-11]。视黄酸(retinoic acid,RA)作为维生素A代谢产生的关键活性产物,能够通过与视黄酸受体(retinoic acid receptor,RAR)、类视黄醇X受体(retinoid X receptor,RXR)结合介导转录调控,从而参与细胞增殖与分化程序,并影响ECM代谢等多个环节[12]。近年来,RA信号通路在调控干细胞命运与软骨发生的作用逐渐受到重视,Lin等[13]研究表明,外源补充RA或激活醛脱氢酶1家族成员A(aldehyde dehydrogenase 1 family member A,ALDH1A)2可增强小鼠等非再生哺乳动物耳廓损伤后的再生能力。此外,有研究表明在梅花鹿饲粮中添加维生素A可显著提高鹿茸产量[14-15]。在AnSCs成软骨分化过程中,RA信号通路可能以阶段性、剂量依赖的方式参与关键分化节点与ECM重塑过程,从而影响鹿茸软骨组织的形成及其生长。因此,本文通过概述鹿茸的生物学特性,阐述RA信号通路的组成和功能,并探讨了其对AnSCs分化及在鹿茸生长过程中的潜在作用,以期为解析RA信号通路在鹿茸生长过程中的调控机制、优化生茸期梅花鹿饲料配方及提高鹿茸产量提供理论依据。

1 鹿茸生长的细胞和组织学基础

鹿茸是哺乳动物中唯一的可完全再生器官,生长速度可达2 cm/d[16-17]。根据组织学特征,鹿茸从上至下可划分5个层区,依次为间充质层(reserve mesenchyme,RM)、前软骨区(pre-cartilage,PC)、过渡区(transition zone,TZ)、软骨区(cartilage area,CA)及矿化软骨区(mineralized cartilage,MC)(也称骨化区)[5,8]。其中,间充质层是提供鹿茸生长的重要细胞来源部位,其厚度在鹿茸生长过程中不断变薄,直至骨化消失[18]。前软骨区存在大量处于不同成软骨分化阶段的AnSCs,从上至下分化程度逐渐升高,过渡区和软骨区分别由正在发育和成熟的软骨细胞组成,而矿化软骨区则主要由成骨细胞和破骨细胞等构成。
在鹿茸生长的不同阶段及不同层区之间,细胞组成和增殖速率、ECM沉积、血管和神经分布、代谢状态等方面均存在差异,这些因素共同决定了细胞命运与组织重塑方向[19-21]。近年来,随着组学技术发展,多项多组学研究进一步揭示了鹿茸发生、发育的细胞组成图谱及其调控规律。Qin等[6]利用单细胞转录组构建了鹿茸再生关键阶段的细胞图谱,发现鹿茸再生早期存在配对相关同源框1(paired-related homeobox 1,PRRX1)阳性间充质干细胞,其可分化产生具有强再生潜能的鹿茸再生祖细胞群(antler blastema progenitor cells,ABPCs),ABPCs在体内外表现出较强自我更新与成骨-成软骨分化能力,提示其可能在驱动鹿茸再生中起着关键作用。此外,该研究还鉴定出SOX9阳性软骨祖细胞、X染色体磷酸盐调节内肽酶同源基因(phosphate regulating endopeptidase homolog X-linked,PHEX)阳性成骨细胞、胶原蛋白Ⅲ型α1链(collagen type Ⅲ alpha 1 chain,COL3A1)阳性成纤维细胞、软骨粘附素(chondroadherin,CHAD)阳性软骨细胞、蛋白酪氨酸磷酸酶受体C型(protein tyrosine phosphatase receptor type C,PTPRC)阳性免疫细胞等多种细胞类群,表明鹿茸再生是多细胞类型协同参与的复杂过程。同样,Zhang等[22]比较生长(60 d)和骨化(90 d)阶段的单细胞转录组测序发现,在鹿茸尖端除AnSCs、软骨细胞、成骨细胞外,还包括大量内皮细胞和周细胞,以及免疫细胞和破骨细胞等群体;在生长阶段,与血管、胶原蛋白组织和细胞分化相关的基因显著上调;在骨化阶段,参与成骨细胞分化、p53信号传导和ATP合成的基因被激活,揭示了鹿茸生长和骨化阶段的基因表达模式的不同。Ba等[8]进一步通过整合单细胞核转录组、单细胞核转座酶可及染色质高通量测序和空间转录组学对AGC系统解析发现,AGC中富含大量的干/祖细胞库,以高增殖状态持续提供软骨发生所需的细胞来源,并以旁分泌的方式释放分子信号物质,同时AGC可构建高度血管化的生态位以支持强血管生成和加速软骨生长,并促进成骨细胞募集,此外,鹿茸的生长涉及到混合骨化的方式,即结合软骨内骨化与直接肥厚软骨细胞到成骨细胞的转分化,其中肥厚软骨细胞可能通过PHEX+中间体产生成骨细胞。因此,从细胞和组织发育的角度考虑,鹿茸的生长是一个AnSCs成软骨分化形成软骨并再次分化成骨的过程。
在上述细胞和组织学基础上,为揭示鹿茸的生长调控机制,国内外学者围绕生长因子或激素对AnSCs的成软骨分化的影响开展了大量研究,发现胰岛素样生长因子-Ⅰ(insulin like growth factor-Ⅰ,IGF-Ⅰ)、转化生长因子-β(transforming growth factor-β,TGF-β)、睾酮、褪黑激素、营养素等可通过Wnt、IGF-Ⅰ等信号通路及软骨形成标志物COL2A1等蛋白调控AnSCs的增殖与分化,并能促进胶原蛋白Ⅱ型(collagen type Ⅱ,COL2)的生成[23-25]。值得注意的是,已有研究证实全反式视黄酸(all-trans retinoic acid,ATRA)可以促进梅花鹿鹿茸软骨细胞的增殖与分化[26],同时,在生茸期提高饲粮维生素A水平可增加梅花鹿鹿茸产量[14-15]。因此,RA信号通路与鹿茸再生、生长过程可能存在紧密联系,但具体机制仍需进一步探究。

2 RA调控鹿茸干细胞成软骨分化的机制

2.1 RA在体内的代谢途径及功能

维生素A家族包括视黄醇(retinol,ROH)、视黄醛(retinaldehyde,RAL)和RA等多种互相转化的形式,其中RA是维生素A在动物机体内的重要活性代谢产物,作为经典的形态发生信号分子,在器官的形成与分化、组织细胞的增殖与凋亡过程中起着重要调控作用[27],是肢体/组织再生过程中的关键调节因子[28-29],但其摄入不足或过量均会引起组织器官发育异常[30]。机体摄入的维生素A在肠道中被水解为ROH,随后ROH与视黄醇结合蛋白(retinol-binding protein,RBP)结合,经过血液运输主要储存在肝脏中,或运送到靶细胞[31]。
在靶细胞内,ROH由多种醇脱氢酶催化氧化为RAL,随后RAL在醛脱氢酶(aldehyde dehydrogenase,ALDH)的作用下进一步不可逆氧化生成RA,该步骤主要由3种ALDH1A同工酶催化,包括ALDH1A1(RALDH1)、ALDH1A2(RALDH2)和ALDH1A3(RALDH3)[32]。生成的RA在细胞内与细胞视黄酸结合蛋白(cellular retinoic acid binding protein,CRABP)结合,被转运到细胞核[33]。在细胞核内,RA与RAR、RXR结合形成异源二聚体复合物,结合视黄酸反应元件(retinoic acid response elements,RAREs)从而启动或抑制靶基因转录[34-35],最终调控细胞增殖、分化和凋亡等过程。为避免RA累积产生毒性,机体需要依赖关键的细胞色素P450家族成员,包括细胞色素P450家族成员26A1(cytochrome P450 family 26 subfamily A member 1,CYP26A1)、细胞色素P450家族成员26B1(cytochrome P450 family 26 subfamily B member 1,CYP26B1)和细胞色素P450家族成员26C1(cytochrome P450 family 26 subfamily C member 1,CYP26C1)对多余的RA进行代谢降解,主要生成4-羟基-视黄酸(4-hydroxy-retinoic acid,4-OH-RA)和4-氧化-视黄酸(4-oxo-retinoic acid,4-oxo-RA)等代谢产物,进而维持RA在组织细胞中的稳态水平[36](图1)。
图1 RA代谢途径示意图

Vitamin A:维生素A;ROH:视黄醇 retinol;RAL:视黄醛 retinaldehyde;RA:视黄酸 retinoic acid;4-OH-RA:4-羟基-视黄酸 4-hydroxy-retinoic acid;4-oxo-RA:4-氧化-视黄酸 4-oxo-retinoic acid;RAR:视黄酸受体 retinoic acid receptor;RXR:类视黄醇X受体 retinoid X receptor;CYP26A1:细胞色素P450家族成员26A1 cytochrome P450 family 26 subfamily A member 1;alcohol dehydrogenase:醇脱氢酶;aldehyde dehydrogenase:醛脱氢酶;CRABP:细胞视黄酸结合蛋白 cellular retinoic acid binding protein;non-genomic effect:非基因组效应。

Fig.1 Schematic diagram of RA metabolic pathway

RA信号通路在各种细胞功能中起着关键作用,可调节基因转录、细胞分化及蛋白质的翻译后修饰等[37]。研究表明,阻断RA信号通路调节过程会导致多种发育障碍的发生,包括肢体和骨骼缺陷、中枢神经系统异常、眼和颅面缺陷、心脏畸形、前肠内胚层缺陷和肾发育不全等[38]。RA能够诱导人胚胎干细胞向神经前体细胞分化,提示RA在干细胞命运决定与谱系分化中具有关键作用[39]。RA信号通路在斑马鱼咽齿早期的发育过程中起调控作用,尤其是RA信号通路缺少会严重影响咽齿发育,使咽齿不能正常形成[40]。Mancini等[41]在体外人多能干细胞成软骨分化体系中,发现RAR信号通路对肢体发育至关重要,采用RAR小分子激活剂(AGN191183)并优化骨形态发生蛋白2(bone morphogenetic protein,BMP2)添加时序可增强早期软骨发生相关基因表达,并获得表达关节软骨基质蛋白的软骨样组织。Lin等[13]通过比较再生能力强(兔等)与非再生(大鼠、小鼠)耳廓损伤后的再生情况,发现ALDH1A2是影响再生能力的关键基因,通过外源注射RA或在小鼠中激活ALDH1A2基因可诱导耳廓的完全再生(包括软骨及神经组织的重建)。此外,RA信号通路通过抑制成纤维细胞生长因子8(fibroblast growth factor 8,FGF8)确保胚胎在体轴延伸的早期阶段正确发育以及激活前肢发生[42]。因此,RA信号通路的调节对组织的发育及细胞命运调控至关重要。

2.2 RA信号通路在AnSCs成软骨分化中的作用

鹿茸的整个生长过程与胚胎长骨的方式相似,涉及软骨内成骨完成发育[8]。在AnSCs成软骨分化过程中,SOX9为软骨生成的关键调节因子,可靶向调控COL2A1、胶原蛋白Ⅸ型(collagen type Ⅸ,COL9)、胶原蛋白Ⅺ型(collagen type Ⅺ,COL11)、聚集蛋白聚糖(aggrecan,ACAN)和软骨寡聚基质蛋白(cartilage oligomeric matrix protein,COMP)等软骨基质相关基因的表达,从而影响软骨形成进程[43]。根据不同机体的生理状态和靶细胞的类型,RA可以直接或通过转录因子间接调控基因转录表达[44-45]。已有研究表明,ATRA可调控软骨发育的关键基因SOX9、COL2A1等的表达[46]。同时,已有体内试验证实饲喂维生素A或向鹿角柄周围注射ATRA可以促进初角茸或再生鹿茸生长[47-48],并调控鹿茸组织中软骨细胞、成骨细胞和破骨细胞的分化[49]。Si等[14]研究表明,在梅花鹿饲粮中添加维生素A可显著提高鹿茸产量,并且参与将ROH转化为RAL、RA的相关基因显著上调,包括视黄醇脱氢酶13(retinol dehydrogenase 13,RDH13)、短链脱氢酶/还原酶家族16C成员5(short chain dehydrogenase/reductase family 16C member 5,SDR16C5)、脱氢酶/还原酶(dehydrogenase/reductase,DHRS)、ALDH1A等。此外,Zhang等[50]对鹿茸不同发育阶段差异基因进行加权基因共表达网络分析(weighted gene co-expression network analysis,WGCNA)后发现,骨化阶段相关模块的模块基因在RA受体信号通路中显著富集。Allen等[47]发现在鹿茸的各分化阶段均含有较高水平的维生素A,且在鹿茸的不同层区(茸皮、前软骨区、软骨区、骨化区)均检测出了ATRA或4-oxo-RA,同时,鹿茸间充质层、软骨区高度表达RARα、RXRβ等。以上结果表明,鹿茸各层组织中存在内源性维生素A及其代谢产物,并可能通过旁分泌的方式参与鹿茸的生长与分化调控。此外,张虹亮[26]研究发现,ATRA可活化RARα和RXRα受体进而通过BMP2-Wnt4-Runt相关转录因子1(Runt-related transcription factor 1,RUNX1)信号通路诱导鹿茸软骨细胞的分化。同样,Williams等[51]通过比较软骨和软骨肥大区等部位参与ROH合成、运输和降解的基因产物的表达发现,ALDH1A2在软骨周围高度表达,而软骨肥大区等几乎无法检测到。以上结果提示,不同细胞类型与不同发育阶段的RA反应性往往表现出显著差异[52-53]。因此,RA信号通路可参与鹿茸生长调控,但RA信号通路对AnSCs成软骨分化效率的作用机制仍需进一步研究。

3 小结与展望

本文通过论述鹿茸生长的细胞和组织学基础,归纳了RA信号通路相关受体、代谢酶与通路基因在鹿茸生长过程中的动态变化,总结了RA信号通路在调控AnSCs成软骨分化中的潜在作用。尽管现有研究提示外源ATRA或生茸期提高饲粮维生素A水平与鹿茸生长和产量改善相关,但关于RA信号通路在鹿茸发育过程中的成软骨分化、ECM重塑与成软骨向成骨转换等关键环节中的作用、关键靶基因网络和层区特异性调控规律仍缺乏系统阐明。
未来研究可围绕鹿茸不同生长阶段与不同层区的RA及其代谢产物水平变化、关键代谢节点分子及受体亚型的表达与定位开展系统分析,并结合单细胞转录组、空间转录组等组学手段,明确RA浓度变化与成软骨分化程度、ECM沉积强度及骨化程序启动之间的关系。进一步可在AnSCs及鹿茸软骨细胞体系中结合外源因子处理与基因调控等方法,对受体及关键代谢节点进行功能验证,阐明RA信号通路对SOX9和COL2A1等软骨发生关键通路、COL10A1相关肥大表型以及ECM合成与降解平衡的直接影响,并解析RA信号通路与Wnt、BMP2等与细胞分化相关信号通路之间的互作关系。以期为生茸期梅花鹿维生素A营养补充的科学应用、饲粮配方优化以及鹿茸产量与品质提升提供理论基础与试验支撑,并为梅花鹿营养调控与养殖效益提升提供新的研究思路。

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