https://www.orthopedic.theclinics.com/article/S0030-5898(09)00071-6/pdf

The Concept of Induced Membrane for Reconstruction of Long Bone Defects

Recently, the first clinical reports on bone regeneration by two recombinant human bone morphogenetic proteins (rhBMPs), BMP-2 and BMP-7 (also named osteogenic protein-1, OP-1) have been published (1-4). Although both BMPs were able to support bone regeneration, a significant variation in individual response was observed with both proteins. Animal studies and laboratory experiments reveal a number of conditions that influence the osteoinductivity of BMP, such as BMP concentration, carrier properties and influence of local and systemic growth factors and hormones. In this paper, these studies and the clinical reports are reviewed, and the conditions that modulate the BMP-dependent osteoinduction are discussed. The information may provide clues as to how the performance of recombinant human BMP as bone-graft substitute in humans can be improved.

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Bone morphogenetic proteins in human bone regeneration.

Growth factors for bone growth and repair: IGF, TGFβ and BMP

During the past decade we and others have shown that bone is a storehouse for growth factors. Accordingly, bone contains a number of growth factors including insulin-like growth factors I and II (IGF-I, IGF-II) transforming growth factor (TGF-beta 1, TGF-beta 2), platelet-derived growth factor, basic and acidic fibroblast growth factor, and bone morphogenetic proteins (BMPs). Osteoblasts have been shown to produce many of these growth factors, which then act in an autocrine and paracrine fashion. The production of these growth factors is regulated by both systemic hormones and local mechanical stress. Recent studies on the relative distribution of bone growth factors during different physiologic and pathologic situations indicate that the concentration of bone growth factors is not invariant and provide indirect evidence that growth factors deposited in bone have physiologic significance. In addition, many of these bone growth factors have been shown to increase bone formation either systemically or locally in vivo. Based on the past findings, we propose that different growth factors may have a specific role in regulating proliferation and differentiation of different stages of osteoblast lineage cells and play important roles in the local regulation of bone formation.

Growth factors to stimulate bone formation

Cell condensation is a pivotal stage in skeletal development. Although prechondrogenic condensations normally exist for some 12 h, duration can vary. Variation is seen both between condensations for different cartilages (Meckel's vs. elastic ear cartilage) and within a single condensation from which more than one skeletal element will form, as in the three components of the single first arch chondrogenic condensation. Understanding how duration of the condensation phase is established--how the condensation phase is entered and exited during cell differentiation--remains a major area for future study. During chondrogenesis, cell-specific products such as collagen types II and IX and cartilage proteoglycan appear concomitant with condensation. Therefore, during chondrogenesis, condensation precedes commitment of cells as prechondroblasts. During osteogenesis, however, differentiation of preosteoblasts precedes condensation. Therefore, during osteogenesis, condensation amplifies the number of committed osteogenic cells. Further comparative analysis of skeletogenesis should provide us with a more rigorous understanding of cell commitment, when differentiation is initiated, how commitment and differentiation are measured and the relationship of condensation to onset of differentiation. Current knowledge of molecules characteristic of condensations focused attention on extracellular matrix and cell surface components on the one hand, and on growth factors homeobox genes and transcription factors on the other. We have drawn together the molecular data for pre-chondrogenic condensations in diagrammatic form in Figure 2. Three major phases of chondrogenesis are identified: (a) epithelial-mesenchymal interactions that precede condensation, (b) condensation itself, and (c) cell differentiation. Although we label the third phase differentiation, it is important to recognize that phases a and b also constitute aspects of chondroblast cell differentiation (see Dunlop and Hall, 1995 for a discussion of this point. The pre-condensation phase is characterized by expression of Hox genes, growth factors (TGF-beta and BMP-2) and the cell surface proteoglycan receptor, syndecan-1. Expression of Msx-1 and Msx-2, growth factors and syndecan continues into the condensation phase. Other molecules, such as versican, syndecan-3 and tenascin, present in low concentrations before condensation, are up-regulated during condensation. Yet other molecules--Hox genes, transcription factors, growth factors (activin, BMP-4 and -5, GDF-5), cell adhesion molecules and proteoglycans--are only expressed during the condensation phase, while the transcription factor Pax-1, fibronectin, hyaluronan and hyaladherin are expressed both during and after condensation. During condensation mRNAs for collagen types II and IX and for the core protein of cartilage proteoglycan are up-regulated. Late in condensation and increasingly thereafter, the protein products of these genes accumulate as chondroblasts differentiate (see Fig. 2 for details). Not all the molecules present before, during of after condensation can be placed into causal sequences. Some however can. In Figure 3 we summarize the causal sequences discussed in this paper as they relate to initiation of condensation and to transit from condensation to overt differentiation during chondrogenesis. Condensations form following activation of at least three pathways: (1) Initiation of epithelial-mesenchymal interactions by tenascin, BMP-2, TGF beta-1 and Msx-1 and -2. (2) Up-regulation of N-CAM by activin. (3) Up-regulation of fibronectin by TGF-beta, further enhancing N-CAM accumulation (Fig. 3). It is by these three pathways that condensations are initiated and grow. Transition from condensation to overt cell differentiation is under both positive and negative control (Fig. 3). Syndecan blocks fibronectin and so blocks N-CAM accumulation, preventing accumulation of additional cell

/pdf/divide-accumulate-differentiate-cell-condensation-in-3pax0az3bd.pdf

Divide, accumulate, differentiate : cell condensation in skeletal development revisited

Osteogenic protein-1 stimulates proliferation and differentiation of human bone cells in vitro.

Peptides including Insulin-related Growth Factor-II (IGF-II) are useful in the treatment of bone disorders such as osteoporosis. They may be administered as the sole active ingredient of a pharmacological composition or in conjunction with a bone localising agent such as sodium fluoride, with which they have a synergistic effect.

Use of igf-ii in the treatment of bone disorders

Evidence That Human Bone Cells in Culture Contain Binding Sites for Osteogenic Protein-1

The invention provides homogeneous compositions of a binding protein for insulin-like growth factors (IGFs) I and II, which binding protein inhibits the proliferative effects of IGF-I and IGF-II upon bone cells. The homogeneous protein of the invention is therefore known as inhibitory IGF binding protein, or In-IGF-BP. The invention also provides cloned nucleic acid sequences encoding In-IGF-BP, artificial expression systems for In-IGF-BP and host cells which produce useful quantities of In-IGF-BP. The invention further provides clinical diagnostic assays for IGFs, therapeutic treatments for IGF-responsive tumors, and means for modulating IGF activity upon bone cells.

David J. Baylink

Papers

Osteogenic protein-1 stimulates proliferation and differentiation of human bone cells in vitro.

Use of igf-ii in the treatment of bone disorders

Evidence That Human Bone Cells in Culture Contain Binding Sites for Osteogenic Protein-1

Inhibitory binding protein for insulin-like growth factors