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Angiogenesis in OA


Healthy adult joint cartilage contains neither blood vessels nor nerves. Osteoarthritic cartilage, in contrast, may be invaded by blood vessels from the subchondral bone. The mechanisms underlying cartilage angiogenesis in osteoarthritis are unclear but may involve hypertrophic chondrocyte differentiation  [1]. Active research is under way to identify the factors involved in cartilage angiogenesis.

Normal joint cartilage contains no blood vessels. This characteristic is due to high concentrations within the cartilage of anti-angiogenic factors such as chondromodulin-1 (ChM-1) and thrombospondin-1 (TSP-1) [2], [3]. In osteoarthritis, cartilage angiogenesis is involved in osteophyte development, subchondral bone remodeling, and cartilage mineralization.

Angiogenesis and subchondral plate remodeling

Osteoblasts and osteoclasts express the various isoforms of vascular endothelial growth factor (VEGF) and their receptors, as well as the angiogenesis inhibitor pigment epithelium-derived factor (PEDF)  [4]. These factors are pivotal in angiogenesis and bone remodeling. In addition, several proteins produced by the osteoblasts, including osteocalcin, bone sialoprotein (BSP), and bone morphogenetic protein (BMP)-7 have been found to promote angiogenesis  [5], [6], [7]. We recently reported that osteoblasts from sclerotic osteoarthritic subchondral bone produced larger amounts of VEGF and osteocalcin than did osteoblasts from nonsclerotic subchondral bone  [8]. Increased local production of these factors may explain that blood vessels invade the osteoarthritic subchondral bone.

Angiogenesis and endochondral ossification

Blood vessels have been identified in the CCL of normal joints. However, the presence of blood vessels beyond the tidemark, in noncalcified cartilage, is abnormal  [9]. Osteoarthritic cartilage contains increased numbers of blood vessels and sensory and sympathetic nerve endings, which cross the tidemark  [10]. The development of blood vessels within the osteochondral junction may contribute to trigger endochondral ossification, characterized by chondrocyte hypertrophy, increased alkaline phosphatase activity within cartilage, and microcrystal accumulation  [11]. This mechanism may explain, at least in part, the occurrence of CCL thickening and tidemark duplication.

Cartilage neoinnervation associated with vascular invasion may play a key role in the mechanical pain that is a hallmark of osteoarthritis. Therefore, osteochondral junction angiogenesis holds promise as a target for the treatment of osteoarthritis.

Effect of inflammation mediators on angiogenesis

Inflammation is intimately linked to angiogenesis. Inflammation contributes in several ways to promote tissue angiogenesis. Hypoxia is common at sites of inflammation and can induce angiogenesis by increasing the production of VEGF. In addition, inflammatory cells such as macrophages, which are abundant in the osteoarthritic synovial membrane, produce pro-angiogenic factors  [12]. Furthermore, the cytokine tumor necrosis factor-a (TNF-a) is strongly expressed by macrophages and also promotes angiogenesis  [9]. TNF-a does not induce endothelial cell mitosis and its pro-angiogenic effect is therefore indirect  [13]. In addition, TNF-a may contribute to regulate the expression of the proteolytic enzymes MMP-9 and MMP-14 known to be crucial for vessel progression into the ECM  [14]. According to the prevalent hypothesis, angiogenesis potentiates inflammation. A number of pro-angiogenic factors, including VEGF and FGF-2, also exert proinflammatory effects. Thus, the co-existence of both processes may result in persistent inflammation  [9].


[1] Pesesse L, Sanchez C, Henrotin Y. Osteochondral plate angiogenesis: A new treatment target in osteoarthritis. Joint Bone Spine 2011;78: 144-9. [Pubmed]
[2] Hiraki Y, Shukunami C. Chondromodulin-I as a novel cartilage-specific growth-modulating factor. Pediatr Nephrol 2000;14: 602-5. [Pubmed]
[3] Pfander D, Cramer T, Deuerling D, Weseloh G, Swoboda B. Expression of thrombospondin-1 and its receptor CD36 in human osteoarthritic cartilage. Annals of the Rheumatic Diseases 2000;59: 448-454. [Pubmed]
[4] Tombran-Tink J, Barnstable CJ. Osteoblasts and osteoclasts express PEDF, VEGF-A isoforms, and VEGF receptors: possible mediators of angiogenesis and matrix remodeling in the bone. Biochemical and Biophysical Research Communications 2004;316: 573-579. [Pubmed]
[5] Bellahcene A, Bonjean K, Fohr B, Fedarko NS, Robey FA, Young MF, Fisher LW, Castronovo V. Bone sialoprotein mediates human endothelial cell attachment and migration and promotes angiogenesis. Circ Res 2000;86: 885-91. [Pubmed]
[6] Cantatore FP, Crivellato E, Nico B, Ribatti D. Osteocalcin is angiogenic in vivo. Cell Biol Int 2005;29: 583-5. [Pubmed]
[7] Ramoshebi LN, Ripamonti U. Osteogenic protein-1, a bone morphogenetic protein, induces angiogenesis in the chick chorioallantoic membrane and synergizes with basic fibroblast growth factor and transforming growth factor-beta1. Anatomical Record 2000;259: 97-107. [Pubmed]
[8] Sanchez C DM, Bellahcène A, Castronovo V, Msika P, Delcour JP, Crielaard JM, Henrotin YE. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis and Rheumatism 2008;58 (2): 442-55. [Pubmed]
[9] Walsh DA, Pearson CI. Angiogenesis in the pathogenesis of inflammatory joint and lung diseases. Arthritis Research 2001;3: 147-153. [Pubmed]
[10] Suri S, Gill SE, de Camin SM, Wilson D, McWilliams DF, Walsh DA. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Annals of the Rheumatic Diseases 2007;66: 1423-1428. [Pubmed]
[11] Brown RA, Weiss JB. Neovascularisation and its role in the osteoarthritic process. Ann Rheum Dis 1988;47: 881-5. [Pubmed]
[12] Haywood L, McWilliams DF, Pearson CI, Gill SE, Ganesan A, Wilson D, Walsh DA. Inflammation and angiogenesis in osteoarthritis. Arthritis and Rheumatism 2003;48: 2173-2177. [Pubmed]
[13] Clavel G, Bessis N, Boissier MC. Recent data on the role for angiogenesis in rheumatoid arthritis. Joint Bone Spine 2003;70: 321-6. [Pubmed]
[14] Lehmann W, Edgar CM, Wang K, Cho TJ, Barnes GL, Kakar S, Graves DT, Rueger JM, Gerstenfeld LC, Einhorn TA. Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing. Bone 2005;36: 300-10. [Pubmed]