中国组织工程研究 ›› 2016, Vol. 20 ›› Issue (15): 2197-2205.doi: 10.3969/j.issn.2095-4344.2016.15.010
• 组织构建综述 tissue construction review • 上一篇 下一篇
血管生长细胞因子与股骨头坏死
洪郭驹1，何 伟2，魏秋实2，陈雷雷2
- 1广州中医药大学，广东省广州市 510006；2广州中医药大学第一附属医院，广东省广州市 510407
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收稿日期:2016-02-01出版日期:2016-04-08发布日期:2016-04-08 -
通讯作者:陈雷雷，博士，主治医师，广州中医药大学第一附属医院，广东省广州市 510407 -
作者简介:洪郭驹，男，1990年生，广东省汕头市人，汉族，广州中医药大学在读硕士，主要从事股骨头坏死基础与临床研究。 -
基金资助:国家自然科学基金项目(81473697)
Angiogenic factors in osteonecrosis of the femoral head
Hong Guo-ju1, He Wei2, Wei Qiu-shi2, Chen Lei-lei2
- 1 Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
2 First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510407, Guangdong Province, China
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Received:2016-02-01Online:2016-04-08Published:2016-04-08 -
Contact:Chen Lei-lei, M.D., Attending physician, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510407, Guangdong Province, China -
About author:Hong Guo-ju, Studying for master’s degree, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China -
Supported by:the National Nature Science Foundation of China, No. 81473697
摘要：
文章快速阅读：
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文题释义：
股骨头坏死的病理演变过程：股骨头坏死初始发生在股骨头的负重区，应力作用下坏死骨骨小梁结构发生损伤即显微骨折以及随后针对损伤骨组织的修复过程。造成骨坏死的原因不消除，修复不完善，损伤-修复的过程继续，导致股骨头结构改变、股骨头塌陷、变形，关节炎症，功能障碍。股骨头坏死固然会引起病痛，关节活动和负重行走功能障碍。
股骨头坏死发生率高的原因：这主要由生物力学和解剖学方面的特点来决定的。①负重大。髋关节是人体最大的关节，支撑着整个上半身的质量，而且负重区只占股骨头的1/4，头与臼之间压力较大，长期保持着这种较大的压力，不但容易造成骨结构上的损伤，而且影响局部的血液循环。②剪力大。髋关节不同于其它负重关节那样两骨端关节力线垂直，股骨干与股骨头颈之间形成132°的角，躯干的重力是由髋臼通过股骨头和股骨颈移行至股骨干，力线不垂直，就形成了剪力。因此，头颈所承受的生理压力要比其他关节大得多。③活动范围大。髋关节的活动范围仅次于肩关节，屈曲、后伸、外展、内收、旋转等。活动范围大，损伤的机会也较多。④血供少。股骨头的血供主要依靠囊外动脉环发出的外侧支持带和内侧支持带动脉，血管的吻合支量少且薄弱，当一支血管被阻断而另一支不能及时代偿时，就会造成股骨头的供血障碍，股骨头骨组织失去血液的供养，就形成了缺血性坏死。
背景：多种血管生长细胞因子参与损伤股骨头的愈合。
目的：探索血管生长细胞因子在股骨头坏死中的作用及其作用机制。
方法：应用计算机检索1980年11月至2015年5月PubMed数据库、Google数据库和SpringerLink数据库中的相关文章，检索词为“angiogenic factors，osteonecrosis of the femoral head，vascular endothelial growth factor，angiopoietin-1，fibroblast growth factor-2，hypoxia inducible factor-1，calcitonin gene related peptide and hypoxia inducible factor-1α”。
结果与结论：最终纳入符合标准的文献68篇。骨血管化和骨修复关系密切，而血管化是基于微环境内特定的信号因子。血管内皮生长因子、血管形成素1、纤维生长因子2、血小板衍生生长因子、降钙素基因相关肽、缺氧诱导因子α等血管生长细胞因子已被证实从不同途径调控股骨头中血管化过程，且对股骨头坏死区域修复有重要的作用。
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程 ORCID: 0000-0003-3587-793X(Chen Lei-lei)
引用本文
洪郭驹，何 伟，魏秋实，陈雷雷. 血管生长细胞因子与股骨头坏死[J]. 中国组织工程研究, 2016, 20(15): 2197-2205.
Hong Guo-ju, He Wei, Wei Qiu-shi, Chen Lei-lei. Angiogenic factors in osteonecrosis of the femoral head[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(15): 2197-2205.
Hypoxia inducible factor-1α (HIF-1α): necrosis and hypoxia
Osteonecrosis results from ischemia with a lack of enough oxygen supply. HIF-1α is a critical mediator of the relevant cells responding to micro- environmental hypoxia and plays a significant role in angiogenesis-osteogenesis interaction during bone regeneration[2-3]. Three non-redundant α subunits comprised the HIF family and the expression of HIF-1α protein is sensitive to oxygen[4]. HIF-1a has a widespread expression in multiple human tissues, such as the skeletal system[5-6]. When oxygen concentration drops below certain levels, the expression of HIF-1α progressively increases with continuous decreases of the oxygen tension[7]. Because of the existence of oxygen-dependent pathway, HIF-1a mediates hydroxylation and has been identified as the powerful regulator of the transcriptional response to oxygen deficiency in tissues[8]. Li et al[9] examined whether local deferoxamine administration could promote angiogenesis and bone repair in ONFH and their final results showed the expression of HIF-1α was higher in the treatment group. As the amount of bone in the skeleton has directly positive correlation to the amount of skeletal vascularity, Ryan has shown osteoblasts express as the product of the HIF pathway and promote the vascularization. It suggests that HIF-1α adjusts and controls bone formation through a non-cell autonomous mechanism, which has been proved in animal experiments[2]. Additionally, Radke and his colleagues found HIF-1a protein at the fibrosis area, transitional region, and proximal femur of the reparative interface adjoining the necrotic zone, which is also called sclerosis band[10].
In addition, HIF-1α regulates the activity of a wide range of genes and modulates stem cell proliferation and differentiation[11]. As a DNA-binding transcription factor, HIFs availably mediate the cellular responses for reducing oxygen availability, by transcriptional activation of a multitude of genes. Those genes encode proteins needed for oxygen delivery to tissues and energy metabolism of tissues themselves[12]. HIF-1α-transfected bone marrow stromal cells (BMSCs) can enhance osteogenic and angiogenic activity no matter in vitro or vivo. Ding et al [13] transplanted HIF-1α-transfected BMSCs successfully to enlarge the vascular capacitance and improve bone regeneration in the necrotic area. Besides, several studies have investigated the association of HIF-1a gene polymorphisms with an increased susceptibility of ONFH by analyzing the genotype and allele frequencies of single nucleotide polymorphisms (SNPs). C111A, C1772T and G1790A are discovered not to associate with osteonecrosis[14], and some other types, such as -2755C/A, +41224T/C and +51610C/T, are dramatically associated with idiopathic ONFH in men[15].
Under hypoxic conditions, HIF-1α protein expression is stabilized and accumulated, thus translocated to the nucleus and binding specific promoter moieties of selective genes encoding vascular endothelial growth factor (VEGF)[3]. Since hypoxia is a vital feature of ONFH, we might expect that downstream effectors of HIF-1a regulate the expression of numerous target genes to control angiogenesis, including VEGF.
VEGF: the central factor
The VEGF family is comprised of several members from A to F. And the A-type pays a lot of donation to angiogenesis in ONFH. VEGF, released primarily by endothelial cells, is a heparin-binding homodimeric glycoprotein[16], and acts in a paracrine and autocrine way. Endothelial cells in the necrotic area are the important targets of VEGF and a significant VEGF dependence is demonstrated in newly formed endothelial cells[17].
VEGF and its receptors in endothelial cells enhance and increase lumen formation, in addition to increasing vessel length, which is important for vascular ingrowth into the necrotic area[18-19]. Their ability is not only to promote growth of vascular endothelial cells derived from arteries, veins, and lymphatic vessels, but also to enhance inflammatory activity and other pathological circumstances. Consistent with a role in the regulation of vascular permeability, VEGF induces endothelial fenestration in some vascular beds and in cultured adrenal endothelial cells. During bone formation, the effects of VEGF are complicated and involve direct impacts on bone cells. As previously reported[20], VEGF mRNA in osteoblasts is induced by bone morphogenetic proteins (BMPs). At the moment that VEGF is produced by osteoblasts in response to BMPs, it may couple angiogenesis to bone formation. Conversely, VEGF may induce BMP-2 expression in endothelial cells, suggesting that endothelial cells may play an osteogenic role by a BMP-2-dependent stimulation of osteoblasts. Wang et al [21] discovered that if mRNA expressions decrease, and VEGF and BMP-2 in the femoral head of non-traumatic ONFH will affect bone remodeling. Base on this theory, Yang et al [22] explored a new method for treating avascular necrosis of the femoral head through VEGF transfection. And they found that eukaryotic expression plasmid pCD-hVEGF 165 mixed with collagen was beneficial to the recovery of necrotic femoral head. Jia et al [23] did the similar test in which the VEGF-121 gene was transfected to enhance angiogenesis in bone tissues, and promote blood flow in the necrotic femoral head.
Concerning ONFH, only few studies really focus on SNPs of HIF-1a. On the contrary, VEGF is implicated in vascularization of the necrotic bone, and thus VEGF polymorphisms have been extensively studied. It is shown that some gene polymorphisms of VEGF are associated with ONFH. Kim et al [24] analyzed three polymorphisms (-2578C/A, -634G/C and +936C/T) in VEGF and showed the -634G/C polymorphism in the VEGF promoter was associated with susceptibility to ONFH in the Korean population. However, these patients enrolled were regardless of etiology. Accordingly, Lee et al [25] investigated a correlation between steroid-induced ONFH and VEGF gene polymorphisms through a polymerase chain reaction-restriction fragment length polymorphism analysis, and they concluded that low inducing VEGF haplotypes may evoke an increased risk and high inducing haplotypes have a defense mechanism for the steroid-induced ONFH. Liu et al [26] carried out the same tests in a Chinese population but only focused on -634G/C. VEGFC gene polymorphisms, for example rs1485766, have been discovered to contribute to identifying genetic susceptibly factors of ONFH in Korea[27].
Fibroblast growth factor-2 (FGF-2): bone metabolism and osteoblasts
FGF-2 is a potential angiogenic factor in ONFH to stimulate osteoblast growth and tissue repair, through being combined with its high-affinity tyrosine kinase receptors, FGF receptors. FGF-2 induces endothelial cell proliferation, migration, and angiogenesis and regulates the expression of several molecules which are thought to mediate critical steps during angiogenesis. Studies have demonstrated that FGF-2 expression shows positive correlation with the necrotic area[28]. Wang and his colleagues[29] found that the expressions of FGF-2 mRNA declined in traumatic and nontraumatic ONFH. FGF-2 is expressed widely on the vessel walls and in the bone marrow cells in the reparative interface zone and in the normal zone, and its expression is suppressed in corticosteroid- associated patients[30]. Thus, FGF-2 protein may be an important angiogenesis regulator in the repair of ONFH.
Under the injury environment, the extracellular matrix transfers tensional signals to the FGF-2-activated endothelial cells to allow vascular formation through stimulating DNA synthesis and motility[31-32]. A combination of vascular bundle implantation and a single local injection of FGF-2 has been shown to improve surgical angiogenesis in the necrotic bone[33]. FGFs, such as FGF-2, function as important regulators of bone development, remodeling, and repair. The proliferation and differentiation of osteoblasts are highly associated with FGF-2 that enhances osseous healing[34]. Thus, the FGF-2 is mostly important to inhibit bone growth. Overexpression of transfected FGF-2 in vivo exerts anabolic actions on bone formation[35]. In addition, the combination of FGF-2 and PDPB can effectively promote the repair of femoral head defect in animal experiments[36]. Until now, FGF treatment has been widely used in clinical practices of ONFH. Kuroda et al [37] indicated that a single local injection of rhFGF-2 microspheres enhanced the repair of ONFH and successfully inhibited femoral head collapse, which may be a promising treatment of ONFH. Yang et al [38] also found that transfection of FGF-2 gene enhanced bone angiogenesis, which is useful to ONFH repair.
Platelet derived growth factor-BB (PDGF-BB): from mesenchymal cells to bone formation
PDGF is a systemic and local regulator of skeletal growth, and its ability of binding mesenchymal cells and promoting angiogenesis is crucial for reparative osseous activity[39]. The PDGF family includes PDGF-A, B, C, and D, encoded by four genes located on different chromosomes[40]. PDGF-BB is considered the universal PDGF isoform because of its ability to bind to all known PDGF isotypes.
Reparative osseous activity is characterized by the differentiation of osteoblastic and osteoclastic cell populations, and regulated by an elaborate system of growth factors and cytokines[41]. As platelets aggregate, PDGF increases the proliferation of mesenchymal cells[42]. They activate cell membrane receptors on target cells, including mitogenesis, angiogenesis and macrophage activation[43], and then stimulate original cells to turn into fibroblasts, osteoblasts, chondrocytes, and smooth muscle cells, accomplished by the local release of PDGF into the injury site. In addition, PDGF also has an effect to accumulate and produce collagen in the osteoblast-rich central bone. When being exposed in a short time, PDGF can have the bone anabolic actions but not induce collagen degeneration.
PDGF-BB shows its indirect effects on bone regeneration by inducing functional vessels in vivo[44]. Blood vessels are able to sprout into the target tissue within inflammation circulation. Increasing the expression of angiogenic factors by PDGF-BB, such as VEGF and bFGF, are an important step in bone regeneration, and it is also an important requirement to promote the structural integrity of the vessels. PDGF-BB is co-regulated with VEGF and other angiogenic molecules. With the increasing VEGF expression in vascular endothelial cells, PDGF-BB can induce a potent angiogenic response and target endothelial cells. The bFGF up-regulates PDGF receptors, improves the survival of endothelial cells and stabilizes newly formed capillaries[45]. PDGF can decrease platelet aggregation while releasing at the same time[46]. Therefore, ONFH patients have a significantly higher serum PDGF-BB level detected as one marker of bio-diagnosis[47-48].
Calcitonin gene related peptide (CGRP): neovascularization and ONFH
CGRP is a 37-aminoacid neuropeptide known to extensively exist in the central and peripheral nervous systems. CGRP, secreted by the peptidergic nerve, is the main mediator of bone metabolism[49], and the CGRP receptor has been discovered in macrophages derived from the bone marrow[50]. As CGRP is mostly found in nerves that are linked closely with blood vessels, it can be used in the treatment of ONFH. The CGRP mRNAs, the component of functional CGRP receptor, have been found in macrophages[51-52]. Osteoclasts are proved to derive from monocytes or macrophages. As previously reported, there are correlations to be made between the ability of CGRP to stimulate bone formation and its action on osteoclasts.
It should be mentioned that osteonecrosis is often accompanied with neural lesions. CGRP is an extremely potential and effective vasodilator to release some mediators, which results in formation of edema, improvement of blood flow, and recruitment of inflammatory cells to the local area[53]. A recent study [54] showed that osteonecrosis triggered significant changes in the expression of CGRP in the femoral head, especially within the subchondral bone. Moreover, CGRP showed significant expressional changes within 1 week after steroid application, and this is supposedly the time when osteonecrosis is thought to occur[55]. Wang et al [56] found that CGRP may be markedly affected by the steroid in the ONFH rabbit model, which may play a key role to regulate the process of steroid-induced ONFH by imbalance of bone metabolism, disturbance of the necrotic microcirculation of bone, and disorder of metastatic pain. Li et al [57] observed the effect of combined regulation of the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CGRP genes and found that down-regulation of PPARγ and up-regulation of CGRP were efficient in suppressing adipogenic differentiation of BMSCs and promoting their osteogenic differentiation. Given these, Wang et al[58] constructed a CGRP-recombinant retrovirus vector to investigate the proliferative and osteogenic ability of BMSCs after virus infection, and both mRNA and protein expressions were detected in target cells. These findings may enlighten a novel approach for the prevention of ONFH.
CGRP also promotes tissue healing by up-regulating VEGF expression. Lack of CGRP is associated with decreased gene expression of VEGF and bFGF in the ischemic tissue[59-60]. As mentioned above, this provides an indirect association that CGRP promotes revascularization and bone remodeling, but also reduces adverse inflammatory events.
Angiopoietin-1 (Ang-1): vascular stabilization
Ang-1 is a particular angiogenic factor in promotion and maintenance of structural integrity in the vasculature[61-62]. Among various angiogenic factors, Ang-1 is unique in non-traumatic ONFH for inducing vascular remodeling through highly stimulating angiogenesis. As the primary agonist, Ang-1 makes action to combine the Tie2 tyrosine kinase receptor, which is mainly involved in growing vascular endothelial cells and other subset of hemangioblast[61]. Genetic experiment investigates Ang1-Tie2 regulates vascular engineering, vessel maturation, and shape stabilization during the mid-term embryonic development[63]. Knockout of Ang-1 or Tie2 genes leads to severe defects in the vascular system and subsequently results in catastrophic disease[61]. This matches the requirement of the micro-vascular development in the necrotic area of ONFH. But a recent genetic study discovered that Ang-1 is unhelpful in vasculature maintenance for the healthy adulthoods[64].
Furthermore, Tie2 activates multiple pathways to elicit several downstream effects[61]. Stimulators, including VEGF, will return to regulate the expression of Tie2 and Ang-1[65]. Interrelationship of these relevant factors during biological feedback can be effectively applied for ischemic treatment. VEGF and Ang-1 are families of vascular-specific growth factors that adjust and control the blood vessel growth, maturation and function. Ang-1, co-localized with VEGF, has an anti-inflammatory effect in the vasculature[66]. Ang-1 enables to increase vascular enlargement and resistance to leakage into the cell tissue, whereas VEGF results in leakage and sprouting[67]. VEGF increases the permeability of endothelial cells, whereas Ang-1 counterbalances VEGF-induced endothelial cell permeability at multiple biological levels. Until now, several attempts have focused on Ang-1 either as a recombinant protein or being expressed via gene therapy. Park et al [68] used an intra-osseous injection of COMP-Ang1 to maintain the trabecular structure of the osteoepiphysis and to prevent femoral head collapse by means of promoting angiogenesis and bone remodeling.
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To investigate the role of the nervous system of bone in steroid-induced osteonecrosis in rabbits. Osteoporos Int. 2010;21(12): 2057-2066. [57] Li J, Wang Y, Li Y, et al. The effect of combined regulation of the expression of peroxisome proliferator-activated receptor-γ and calcitonin gene-related peptide on alcohol-induced adipogenic differentiation of bone marrow mesenchymal stem cells. Mol Cell Biochem. 2014;392(1-2):39-48. [58] Wang YS, Wang YH, Zhao GQ, et al. Osteogenic potential of human calcitonin gene-related peptide alpha gene-modified bone marrow mesenchymal stem cells. Chin Med J (Engl). 2011;124(23):3976-3981. [59] Toda M, Suzuki T, Hosono K, et al. Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother. 2008;62(6):352-359. [60] Mishima T, Ito Y, Hosono K, et al. Calcitonin gene-related peptide facilitates revascularization during hindlimb ischemia in mice. Am J Physiol Heart Circ Physiol. 2011; 300(2):H431-439. [61] Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87(7): 1161-1169. [62] Schnürch H, Risau W. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development. 1993;119(3):957-968. [63] Augustin HG, Koh GY, Thurston G, et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009; 10(3): 165-177. [64] Jeansson M, Gawlik A, Anderson G, et al. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest. 2011;121(6):2278-2289. [65] Homer JJ, Greenman J, Drevs J, et al. Soluble Tie-2 receptor levels independently predict locoregional recurrence in head and neck squamous cell carcinoma. Head Neck. 2002;24(8):773-778. [66] Makinde T, Agrawal DK. Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease. J Cell Mol Med. 2008;12(3):810-828. [67] Thurston G. Complementary actions of VEGF and angiopoietin-1 on blood vessel growth and leakage. J Anat. 2002;200(6):575-580. Park BH, Jang KY, Kim KH, et al. COMP-Angiopoietin-1 ameliorates surgery-induced ischemic necrosis of the femoral head in rats. Bone. 2009;44(5):886-892. |
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Non-traumatic osteonecrosis of the femoral head (ONFH) is a devastating disease that is influenced by multiple factors, including steroid administration, alcohol abuse, and vascular injury. Previous studies have suggested that the pathogenic mechanism of ONFH might be related to intravascular thrombus occlusion and extravascular lipid deposition, which results in the damage to the blood supply system[1]. The vasculature in bone tissues is important for skeletal development and growth, modeling and remodeling, and healing processes. To our knowledge, angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. The vasculature supplies oxygen to bone development and regeneration and also delivers critical signals to the stroma that stimulate mesenchymal cell specification to promote bone formation[2]. The bone repair efficiency in ONFH determines the feasibility of restoring the necrotic area. Angiogenic factors are a hallmark of wound healing, menstrual cycle, cancer, and various ischemic and inflammatory diseases, which are an essential component for the healing of damaged femoral heads. A rich variety of pro-angiogenic molecules have already been discovered. This paper briefly provides an overview to systematically highlight the studies on the expression and interactions of angiogenic factors in ONFH.
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
Data source
A computer-based retrieval was
performed by the first author in PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), Google (http://www.scholar.google.com.hk) and SpringerLink (http://springer.lib.tsinghua.edu.cn/) databases for literatures published from November 1980 to May 2015, using the key words of “angiogenic factors, osteonecrosis of the femoral head, vascular endothelial growth factor, angiopoietin-1, fibroblast growth factor-2, hypoxia inducible factor-1, calcitonin gene related peptide and hypoxia inducible factor-1α”.
Data selection
Papers meeting the following criteria were included: papers with contents closely related to this paper; original papers with reliable topics and evidence; or papers with clear points and all-round analysis. Obsolete and repetitive studies were excluded.
Data analysis
A total of 389 papers were acquired by screening titles and abstracts, and finally 68 papers concerning basic theory and both studies in vitro and in vivo were included.
As angiogenesis is a complex process, the involvement of multitudinous angiogenic factors has been an innovative way to understand and treat ONFH (Figure 1). Angiogenic factors aim to rebuild the blood supply and address revascularization fundamentally. At present, cases of ONFH in pre-collapse stage are mostly selected for cytotherapy, in combination with graft implantation or genetic therapy. Although outstanding advances have been achieved in the basic studies and clinical researches, it is premature to conclude an exact answer. Moreover, our final target is not only to assist hip-preservation surgery, but also to successfully realize the target of reconstruction of the biological environment within the femoral head. Many researchers believe that the use of a single factor is insufficient to form a biological environment for neovascularization. Besides VEGF and HIF-1α, some factors that are little known within this region can also be activated if ONFH occurs. All of these factors take part in the process of angiogenesis and their cooperation will have a better result in promoting new vessel formation in the necrotic area of the femoral head.
To our knowledge, this is the first review about biology and clinical applications of angiogenic factors in ONFH. As reported recently, the detailed relationships between them still remain a lot of problems to solve.
Therefore, further explorations are needed in distinguishing angiogenic factors because of their possible functions and other factors which are not included in this review. Large amount of basic studies, including animal experiments and gene research, are required. Moreover, factor-factor and gene-factor interactions should be considered in the future focus, and development in clinical therapeutic techniques will also be an issue of concern. It will provide a new insight into the future studies by establishing the primary mechanisms of angiogenic factors through the inter-pathway regulation.
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
Therefore, further explorations are needed in distinguishing angiogenic factors because of their possible functions and other factors which are not included in this review. Large amount of basic studies, including animal experiments and gene research, are required. Moreover, factor-factor and gene-factor interactions should be considered in the future focus, and development in clinical therapeutic techniques will also be an issue of concern. It will provide a new insight into the future studies by establishing the primary mechanisms of angiogenic factors through the inter-pathway regulation.
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
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文题释义：
股骨头坏死的病理演变过程：股骨头坏死初始发生在股骨头的负重区，应力作用下坏死骨骨小梁结构发生损伤即显微骨折以及随后针对损伤骨组织的修复过程。造成骨坏死的原因不消除，修复不完善，损伤-修复的过程继续，导致股骨头结构改变、股骨头塌陷、变形，关节炎症，功能障碍。股骨头坏死固然会引起病痛，关节活动和负重行走功能障碍。
股骨头坏死发生率高的原因：这主要由生物力学和解剖学方面的特点来决定的。①负重大。髋关节是人体最大的关节，支撑着整个上半身的质量，而且负重区只占股骨头的1/4，头与臼之间压力较大，长期保持着这种较大的压力，不但容易造成骨结构上的损伤，而且影响局部的血液循环。②剪力大。髋关节不同于其它负重关节那样两骨端关节力线垂直，股骨干与股骨头颈之间形成132°的角，躯干的重力是由髋臼通过股骨头和股骨颈移行至股骨干，力线不垂直，就形成了剪力。因此，头颈所承受的生理压力要比其他关节大得多。③活动范围大。髋关节的活动范围仅次于肩关节，屈曲、后伸、外展、内收、旋转等。活动范围大，损伤的机会也较多。④血供少。股骨头的血供主要依靠囊外动脉环发出的外侧支持带和内侧支持带动脉，血管的吻合支量少且薄弱，当一支血管被阻断而另一支不能及时代偿时，就会造成股骨头的供血障碍，股骨头骨组织失去血液的供养，就形成了缺血性坏死。
1 此问题的已知信息：股骨头坏死发生率高的原因。这主要由生物力学和解剖学方面的特点来决定的。①负重大：髋关节是人体最大的关节，支撑着整个上半身的重量，而且负重区只占股骨头的1/4，头与臼之间压力较大，长期保持着这种较大的压力，不但容易造成骨结构上的损伤，而且影响局部的血液循环。②剪力大。髋关节不同于其它负重关节那样两骨端关节力线垂直，股骨干与股骨头颈之间形成132°的角，躯干的重力是由髋臼通过股骨头和股骨颈移行至股骨干，力线不垂直，就形成了剪力。因此，头颈所承受的生理压力要比其他关节大得多。③活动范围大。髋关节的活动范围仅次于肩关节，屈曲、后伸、外展、内收、旋转等。活动范围大，损伤的机会也较多。④血供少。股骨头的血供主要依靠囊外动脉环发出的外侧支持带和内侧支持带动脉，血管的吻合支量少且薄弱，当一支血管被阻断而另一支不能及时代偿时，就会造成股骨头的供血障碍，股骨头骨组织失去血液的供养，就形成了缺血性坏死。
2 文章增加的新信息：血管为骨的生长和发育供应氧气，也提供重要的细胞因子。多种血管生长细胞因子已被证实从不同途径调控股骨头中血管化过程，且对股骨头坏死区域修复有重要的作用。
3 临床应用的意义：血管生长细胞因子是一种在未来发展中极具前景的修复坏死领域的生物方法。
中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
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