The current and future therapies of bone regeneration to repair bone defects

Abstract

Bone defects often result from tumor resection, congenital malformation, trauma, fractures, surgery, or periodontitis in dentistry. Although dental implants serve as an effective treatment to recover mouth function from tooth defects, many patients do not have the adequate bone volume to build an implant. The gold standard for the reconstruction of large bone defects is the use of autogenous bone grafts. While autogenous bone graft is the most effective clinical method, surgical stress to the part of the bone being extracted and the quantity of extractable bone limit this method. Recently mesenchymal stem cell-based therapies have the potential to provide an effective treatment of osseous defects. In this paper, we discuss both the current therapy for bone regeneration and the perspectives in the field of stem cell-based regenerative medicine, addressing the sources of stem cells and growth factors used to induce bone regeneration effectively and reproducibly.

Figure 1

The schematic outlines of the bone remodeling cycle and the balance of bone resorption and bone formation. (a) In bone tissue, the osteoblasts are involved in new bone formation, while osteoclasts play a major role in bone resorption. The first step in the bone remodeling cycle is the resorption of existing bone by osteoclasts, followed by formation of the cement line in resorption lacunae and osteoblasts. Each cell type seems to be regulated by a variety of hormones and by local factors. (b) If the balance between bone formation and resorption is lost by the uncontrolled production of regulators, bone structure would be strikingly damaged, and the subject would be susceptible to osteoporosis and osteopetrosis.

Figure 2

A schematic model for the differentiation of mesenchymal stem cells into tissue-specific cells by specific transcriptional factors. Mesenchymal stem cells can differentiate into osteoblasts, chondrocytes, myoblasts, and adipocytes. Each differentiation program is regulated by specific transcription factors: Runx2/Osterix, Sox5/6/9, MyoD family, and PPARγ, respectively.

Figure 3

A model of NF-κB-mediated inhibition of BMP/Smad-mediated DNA binding activity. NF-κB, particularly the p65 subunit, binds the Smad1/Smad4 complex directly or indirectly, and that this binding interferes with the DNA binding of Smad proteins induced by BMP-2.

Figure 4

BMP2-induced ectopic bone formation in vivo is enhanced in the presence of a selective inhibitor of NF-κB, BAY11-7082. Two micrograms of BMP2 was implanted subcutaneously to induce ectopic bone formation in the presence or absence of BAY11-7082 in mice (n = 8). (a) μCT reconstruction images of ectopic bone in the presence or absence of BAY11-7082 in mice. Bar: 1 mm. (b) Bone mineral density (BMD) of the ectopic bone in the presence or absence of BAY11-7082 was measured by dual-energy X-ray absorptiometry (DXA). *P < 0.01.