Faculty Bibliography

The hedgehog family of morphogens (sonic [Shh], Indian, and desert hedgehog) are central regulators of embryologic growth and tissue patterning. Although recent work implicates Shh in postnatal tissue repair and development, conclusive evidence is lacking. Here, we demonstrated the importance of Shh in wound repair, by examining the effects of cyclopamine, a specific inhibitor of the Shh signaling cascade, on tissue repair. Using a murine-splinted excisional wound model, which attenuates wound contraction in this loose-skinned rodent, we established that, by all measures (wound closure, epithelialization, granulation formation, vascularity, and proliferation), wound healing was profoundly impaired when Shh signaling was disrupted. Because embryonic disruption of Shh is associated with distinct phenotypic defects, our findings invite investigation of the potential role of Shh signaling under postnatal conditions associated with disregulated wound healing

The bony biochemical environment is a complex system that permits and promotes cellular functions that lead to matrix production and ossification. In Part I of this review, we discussed the important actions of signaling molecules, including hormones, cytokines, and growth factors. Here, we review other constituents of the extracellular matrix, including minerals, fibrinous and nonfibrinous proteins, and enzymes such as the matrix metalloproteinases. We conclude with a discussion of the role of biochemical modulation in endogenous and exogenous tissue engineering

While it has been long appreciated that biomechanical forces are involved in bone remodeling and repair, the actual mechanism by which a physical force is translated to the corresponding intracellular signal has largely remained a mystery. To date, most biomechanical research has concentrated upon the effect on bone morphology and architecture, and it is only recently that the complex cellular and molecular pathways involved in this process (called mechanotransduction) are being described. In this paper, we review the current understanding of bone mechanobiology and highlight the implications for clinical medicine and tissue engineering research

The bony biochemical environment is an active and dynamic system that permits and promotes cellular functions that lead to matrix production and ossification. Each component is capable of conveying important regulatory cues to nearby cells, thus effecting gene expression and changes at the cytostructural level. Here, we review the various signaling molecules that contribute to the active and dynamic nature of the biochemical system. These components include hormones, cytokines, and growth factors. We describe their role in regulating bone metabolism. Certain growth factors (i.e., TGF-beta, IGF-1, and VEGF) are described in greater detail because of their potential importance in developing successful tissue-engineering strategies

BACKGROUND:: Successful bone engineering requires an understanding of the effects of mechanical stress on osteoblast differentiation. Therefore, we examined the effects of varying magnitude and duration of fluid shear stress on factors associated with osteoblastic differentiation. METHODS:: Using a cone viscometer, primary neonatal rat calvarial osteoblasts were exposed to continuous fluid shear stress at varying doses: 0.21, 0.43, and 0.85 Pa for varying time periods. Gene expression was analyzed using Northern blots and nitric oxide production was quantified with the colorimetric Griess reaction. RESULTS:: Fluid shear stress stimulated comparable transient increases in TGF-beta1 and TGF-beta3 expression by 3 hours. TGF-beta1 expression returned to baseline by 12 hours at all shear doses. In contrast, TGF-beta3 expression decreased by 22 percent and 47 percent at 12 hours in response to 0.43 Pa and 0.85 Pa, respectively. Osteopontin and Msx-2 expression patterns were consistent with a more differentiated phenotype at all shear levels. The maximum level of shear stress increased nitric oxide production 2.5-fold at 12 hours and 6.0-fold at 24 hours. CONCLUSIONS:: These data demonstrate differential regulation of TGF-beta1 and TGF-beta3 isoforms with fluid shear stress. Furthermore, because osteopontin and Msx-2 changes were consistent with progressive differentiation at all levels of shear stress, dosage appears to be less important than the presence of an effective physical stimulus. Lastly, nitric oxide does not appear to be the primary regulator of early transcriptional changes found in this study