Role of morphogenetic proteins in skeletal tissue engineering and regeneration

Abstract

Morphogenesis is the developmental cascade of pattern formation and body plan establishment, culminating in the adult form. It has formed the basis for the emerging discipline of tissue engineering, which uses principles of molecular developmental biology and morphogenesis gleaned through studies on inductive signals, responding stem cells, and the extracellular matrix to design and construct spare parts that restore function to the human body. Among the many organs in the body, bone has considerable powers for regeneration and is a prototype model for tissue engineering. Implantation of demineralized bone matrix into subcutaneous sites results in local bone induction. This model mimics sequential limb morphogenesis and has permitted the isolation of bone morphogens, such as bone morphogenetic proteins (BMPs), from demineralized adult bone matrix. BMPs initiate, promote, and maintain chondrogenesis and osteogenesis, but are also involved in the morphogenesis of organs other than bone. The symbiosis of the mechanisms underlying bone induction and differentiation is critical for tissue engineering and is governed by both biomechanics (physical forces) and context (microenvironment/extracellular matrix), which can be duplicated by biomimetic biomaterials such as collagens, hydroxyapatite, proteoglycans, and cell adhesion glycoproteins, including fibronectins and laminin. Rules of tissue architecture elucidated in bone morphogenesis may provide insights into tissue engineering and be universally applicable for all organs/tissues, including bones and joints.

Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats

“…At all the time-points measured, BMD Gene Therapy in the defect area of the experimental group was significantly higher compared with the control group 2-4 weeks after implantation (P Ͻ 0.001). In control rats, BMD increased slowly between weeks 2 and 3, from 4.3 ± 0.7 mg/cm 2 to 10.6 ± 1.9 mg/cm 2 , followed by a more rapid increase between weeks 3 and 4, to 29.6 ± 7.0 mg/cm 2 .…”

“…Among the most potent growth factors that stimulate bone formation are the BMPs, multifunctional cytokines which are members of the transforming growth factor (TGF)-␤ superfamily. 1,2 The osteoinductive potential of BMPs, especially BMP2, BMP4 and BMP7, makes them clinically valuable as alternatives to bone grafts. [3][4][5][6] In order to promote the healing of fractures or the fillingin of large bone defects, the BMPs should be delivered at adequate concentrations for a period of time sufficient to induce a strong bone formation response.…”

Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery

“…Bone also undergoes continuous remodeling throughout life. 2,3 Three major types of cells are present in bone tissues: boneforming osteoblasts, bone-resorbing osteoclasts, and chondrocytes. Osteoblasts are derived from the mesenchymal stem cells, which also serve as precursor cells for myocytes, adipocytes, and chondrocytes.…”

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

“…Implantation of BMP can elicit new bone formation both in orthotopic and heterotopic sites [13,27], and is used as a bone graft substitute in the clinical setting [8,24,30]. Although it is now possible to generate recombinant human BMPs for medical use, more than 1.5 mg/kg of the recombinant protein has been required for bone induction in primates [1,15], probably due to their reduced capability for tissue regeneration.…”