ReviewRole of angiogenesis in bone repair
Section snippets
Bone Circulation and Angiogenesis
Vasculature is essential for embryonic skeletal development, bone growth and remodeling [1], [2], [3], [4]. Apart from supplying the bone tissue with nutrients, growth factors, hormones, cytokines and chemokines as required; and removing waste products, bone vasculature acts as a communicative network between the bone and neighboring tissues [3], [5]. Depending on their origin, bone development occurs via two distinct modes of ossification: Intramembranous (flat bones such as skull and
Normal bone repair and microenvironment
In the event of an injury, bones have the unique ability to heal by regenerating new bone sans development of fibrotic scars, a common phenomenon during soft tissue healing [1], [5], [38]. The development of fibrotic scars during bone repair results in critical-sized bone defects if left untreated and it would ultimately compromise the mechanical properties of the skeleton [5]. Hence adult bone repair mimics bone formation during organogenesis, consisting of a series of interdependent healing
Pro-angiogenic signaling in bone wound micro-environment
A plethora of pro-angiogenic factors such as the VEGF, Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor β (TGF-β), Fibroblast Growth Factors (FGF) and Bone Morphogenetic Proteins (BMPs) are involved in the bone repair cascade (see Fig. 2). Their role in initiating angiogenesis and/or regulating osteogenesis has been summarized in Table 1.
Among these, VEGF, whose production is frequently stimulated by most osteoinductive factors [67], [68], [69], has been suggested to possibly
Endothelial progenitor cells in bone repair
EPCs are a population of cells that is found circulating in the bone marrow and peripheral blood, which has the ability to differentiate into mature EC. New blood vessels during fracture repair can be formed either via angiogenesis or vasculogenesis. The latter process occurs when new blood vessels form without a pre-existing vascular component and occurs via the differentiation of local or/and circulating EPCs [132], [133], [134], [135], [136]. EPC are comprised of a heterogeneous population
Current therapeutic tools in bone repair and their limitations
The treatment for restoring bone function is often dependent on the type of orthopedic injury. Although bone fractures generally undergo repair via the process of callus formation [38], severe cases of bone damage (traumatic fractures, bone tumors etc) mostly require surgical reconstruction [52]. Current therapy involves bone grafting, a procedure that replaces missing bone with either autologous (bone material sourced from patients own body), allogenic (bone material sourced from a donor) or
Strategies for improving vascularization in Bone tissue engineering
Biomaterial scaffolds in bone tissue engineering serve as templates for the establishment of the vascular system and bone-forming cell growth [160]. Lack of de novo tissue growth, insufficient nutrient supply and poor waste removal in 3D scaffolds are some of the limitations still hampering successful bone engineering and transplantation. The efficacy of the scaffolds for successful bone regeneration critically depends on their ability to induce and support vascular infiltration. Various
Incorporation pro-angiogenic factors in scaffolds
The close association between angiogenesis and osteogenesis, makes angiogenic growth factors that are implicated in both neovascularization and endochondral ossification, important therapeutic agents for bone regeneration. The ability of pro-angiogenic factors like VEGF, FGF-2, BMP-2 and BMP-7 to accelerate fracture repair when administered exogenously is well established [45], [46], [67], [70], [89], [99], [100]. For example injecting FGF-2 into larger animal models was reported to
‘Biocoating’ of scaffolds
Generating vascularized engineered bone tissue constructs by culturing MSCs or co-culturing ECs and bone cells in scaffolds presents another approach to simultaneously promote osteogenesis and vascularization [194], [195], [196]. ECs are well established to play a key role in angiogenesis, thus enhancing EC migration into the matrix to develop vascular beds is critical for the survival of implanted bone constructs. Schechner et al. [197] observed that in vivo implantation of primitive vascular
Gene therapy
The application of gene therapy as a mean to deliver growth factors for the clinical management of orthopedic disorders is another promising area in the field of bone tissue engineering [226]. The transference of genetic material can be performed by either in vivo or ex vivo gene-transfer procedure, implemented via viral (transfection) or non-viral (transduction) vectors [227], [228]. The in vivo technique where the genetic material is directly transferred to the host is generally the easier of
Conclusions
In conclusion, while much of the current strategies for fabricating functional vascularized bone grafts are still in their infancy, experimental data offers great potential for their future application in treatment of bone repair. However, in order to accelerate our progress in the field it is imperative to obtain a better understanding of bone wound microenvironment, which is the home of biological processes underlying vascularization and bone regeneration during fracture repair. This will in
Acknowledgments
The authors would like to acknowledge the help of Saranya Rajendran, Prattusha Sengupta, Sneha Srinivas and Ilaria Salvati for editing the manuscript. This work was partially supported by FP7-PEOPLE-2011-IRSES; Grant No 295181 – Acronym: INTERBONE, and a grant from University Grant Commission (UGC) Faculty Recharge Programme, Government of India to SC.
References (233)
- et al.
Cytokine Growth Factor Rev.
(2013) - et al.
Trends Cardiovasc. Med.
(2000) Joint Bone Spine
(2002)- et al.
Blood
(1999) - et al.
Blood
(2000) - et al.
Bone
(2002) - et al.
Best Pract. Res. Clin. Endocrinol. Metab.
(2008) - et al.
Semin. Cell. Dev. Biol.
(2008) - et al.
Bone
(2009) - et al.
Dev. Cell
(2010)
Trends Mol. Med.
Semin. Cell. Dev. Biol.
Injury
Bone
Bone
Bone
J. Craniomaxillofac. Surg.
Exp. Hematol.
Bone
Mol. Cell. Endocrinol.
FEBS Lett
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Biochem. Biophys. Res. Commun.
J. Orthop. Res.
Mech. Dev.
Birth Defects Res C Embryo Today.
PLoS ONE
Journal of Bone and Mineral Research
Calcif. Tissue Int.
J. Anat.
J. Bone Miner Res.
Nat. Rev. Immunol.
Nippon Seikeigeka Gakkai Zasshi
Br. J. Haematol.
Nat. Med.
J. Bone Miner. Res.
Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL
Proc. Natl. Acad. Sci. USA
J. Bone Miner. Res.
Haematologica
Cited by (281)
Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice
2024, Archives of Biochemistry and BiophysicsAngiogenic and immunomodulation role of ions for initial stages of bone tissue regeneration
2023, Acta Biomaterialia