Bone morphogenetic proteins and the induction of periodontal tissue regeneration

Abstract

Since antiquity, bone has been known to have a remarkable potential for repair and regeneration (28). Tissue engineering, defined as the science of fabrication of new tissues for replacement and the regeneration of lost or destroyed tissues, has learned and is still learning, the secrets of its principles from bone repair and regeneration, and it is likely that more secrets still remain to be learned from the principles of bone tissue engineering (27, 28). What are the rules that sculpt tissue morphology and engineer the architecture of mineralized tissues? The three critical ingredients for optimal tissue engineering are soluble molecular signals, responding cells with associated cell-surface receptors, and assembly of the extracellular matrix (27, 28). The accrued knowledge can now be applied not only to bone regeneration, but also to alveolar bone with associated cementum and periodontal ligament regeneration, tissues that are known to be recalcitrant to heal and regenerate (2, 38, 39). The complex tissue morphologies of the periodontal tissues are a superb example of design architecture and engineering. The supportive alveolar bone consists of cortical or compact bone and cancellous or trabecular bone. The periodontal ligament system, epitomized by inserting Sharpey’s fibers into the cementum, provides a gomphosis that uniquely articulates the tooth to the alveolar bone and permits mechanical function and adaptation to changing mechanical environments and signals additionally modulated by the avascular mineralized root cementum (2, 37–39). Substantial knowledge has now been gained about the molecular signals that determine the emergence of the complex tissue morphologies during regeneration of the periodontal tissues (2, 17, 39, 44, 51). The molecular mechanisms for such regeneration are the osteogenic proteins of the transforming growth factor-b superfamily (26, 32, 33, 35, 39, 50, 51), of which the bone morphogenetic and osteogenic proteins (BMPs/OPs) are a class of powerful inducers of endochondral bone differentiation (Fig. 1) (25, 31, 35, 36, 40, 71). Pioneering experiments gave rise to the fascinating phenomenon of bone formation by induction (64, 65). Unexpectedly, the ligature of the renal artery in rabbits induced transformation of the kidney into bone with marrow (53). Acid alcohol bone extracts, implanted intramuscularly in rabbits, induced de novo bone formation (13), and Lacroix hypothesized that bone contains substances, which he named osteogenins, that initiate bone growth and differentiation (13). Urist (64) made the key discovery that demineralized bone matrix, when implanted heterotopically in intramuscular sites of allogeneic rat recipients, induces de novo endochondral bone formation by induction (64, 65). Reddi and Huggins (29) showed that subcutaneous implantation of demineralized bone matrix results in de novo local endochondral bone differentiation, with the associated molecular and biochemical changes correlating with each morphological step of bone differentiation by induction (23, 24). There is a direct relationship between differentiation in early development and regeneration in postnatal life. Fracture repair recapitulates events that occur during the normal course of embryonic bone development (6, 23, 24, 26, 28, 67). The tissue response elicited by heterotopic implantation of demineralized bone matrix is reminiscent of embryonic bone development (Fig. 1) (6, 23, 24, 26, 28, 32, 67). Unlike the epiphyseal growth plate, however,