Potential roles of bone morphogenetic proteins (BMPs) in skeletal repair and regeneration

Bone morphogenetic protein (BMP) was originally discovered by Urist in 1965 as a bone-inducing substance in an ectopic site [1], and the term "BMP" was first described by Urist and Strates in 1971 [2]. By 1988, molecular clones, as well as the amino-acid sequences of BMP had been characterized from a highly purified preparation obtained from bovine bone [3]. In 1993, murine molecular clones from murine osteosarcoma had also been identified, and they became available for animal experimental systems [4,5] and enabled the performance of various investigations based on molecular technologies. To date, at least 20 members of the BMP family have been identified. In addition to its bone-inducing activity, BMP is now thought to have essential and multifunctional roles in various other organs during morphogenesis. Now, "BMP" should be better recognized as "body morphogenetic protein" [6]. From the viewpoint of clinical applications in orthopedic medicine, several members of the BMP family are attracting considerable attention as promising therapeutic tools for skeletal regeneration and as target molecules for the treatment of skeletal disorders. Previous investigations showed that BMP-2, -4, and -7 stimulated osteogenic and chondrogenic differentiation via BMP receptor (BMPR) types I and II [7-9]. Smad mediates the intracellular signaling of these BMPs [10]. Another BMP, cartilage-derived morphogenetic protein (CDMP)-1 also known as growth and differentiation factor-5 (GDF-5), reportedly shows unique activities, such as the promotion of chondrogenic differentiation and the induction of tendon tissue in vivo [11,12]. Recombinant BMP-2 and -7 proteins have already been in clinical use in the United States and Europe for problematic trauma cases such as open fractures and nonunions [13,14]. The clinical outcomes have been reported as encouraging. This article reviews the current findings regarding BMP signaling underlying the process of skeletal repair and regeneration. Which BMPs are involved, and in what manner are they involved in the process of bone repair and regeneration? How are BMPs induced in various orthopedic conditions? In some instances, the BMPs play physiological roles, while in other instances, they play pathological roles. The findings will provide a key to understanding the physiological and pathological natures of BMPs and BMP signals in various orthopedic conditions, leading to novel therapeutic formulations aimed at less invasive and more promising treatment of orthopedic injuries and disorders.