Abstract
Transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) have opposing but complementary functions in directing bone growth, repair, and turnover. Both are found in the bone matrix. Proteins that bind to and affect the activity of these growth factors will determine the relative abundance of the growth factors and, therefore, regulate bone formation. Secreted phosphoprotein 24 kD (Spp24) is a bone matrix protein that has been demonstrated to bind to and affect the activity of BMPs. The arginine-rich carboxy terminus of Spp24 is proteolytically processed to produce three other predictable truncation products (Spp18.1, Spp16.0, and Spp14.5). In this work, we report that kinetic data obtained by surface plasmon resonance demonstrate that Spp24 and the three C-terminal truncation products all bind to TGF-β1 and TGF-β2 with a similar but somewhat less affinity than they bind BMP-2; that, as in the case of BMP-2, the full-length (FL) form of Spp24 binds TGF-β with greater affinity than do the truncation products; that FL-Spp24 inhibits TGF-β2 induced bone formation in vivo, but Spp14.5 does not; and that co-administration of FL-Spp24 or Spp14.5 with TGF-β2 in vivo is associated with a reduction in the amount of cartilage, relative to new bone, present at the site of injection. This finding is consistent with the observation that low-dose TGF-β administration in vivo is associated with greater bone formation than high-dose TGF-β administration, and suggests that one function of Spp24 and its truncation products is to down-regulate local TGF-β activity or availability during bone growth and development. The similarities and differences of the interactions between Spp24 proteins and TGF-β compared to the interaction of the Spp24 proteins and BMPs have significant implications with respect to the regulation of bone metabolism and with respect to engineering therapeutic proteins for skeletal disorders.
Highlights
Mature, mineralized bone contains a number of growth factors that are essential for proper bone remodeling and repair [1]
The kinetics of the binding of FL-Secreted phosphoprotein 24 kD (Spp24) and its degradation products to TGF-β1 and -β2 were determined by surface plasmon resonance (Figure 1, Table 1), and the results are compared to those obtained with recombinant human bone morphogenetic proteins (BMPs)-2, which were previously published [15,18]
Given the relatively equivalent concentrations of TGFβs and BMPs in bone [6,7], the kinetics of binding suggest that Spp24 and its degradation products would bind BMPs at lower concentrations than transforming growth factor-β (TGF-β), achieving a relative sequestration of BMPs when compared to free TGF-βs
Summary
Mature, mineralized bone contains a number of growth factors that are essential for proper bone remodeling and repair [1] Among these growth factors, bone morphogenetic proteins (BMPs), especially BMP-2 and -7, and transforming growth factor-β (TGF-β), are the most significant. Recombinant BMPs such as BMP-2 and -7 enhance osteoblast differentiation [4] but are capable of inducing the entire recapitulation of endochondral bone formation as originally described by Urist [5]. This process involves stem cell proliferation, chondrogenic differentiation, and replacement of cartilage by bone. No such group of proteins has yet been described in relation to the BMPs
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