Tribute to Dr. Marshall Urist: Musculoskeletal Growth Factors: Editorial Comment

Abstract

Growth factors are triggering and/or signaling molecules that regulate not only growth but also musculoskeletal repair and regeneration. Bone morphogenetic proteins (BMPs), which regulate cellular proliferation, differentiation and extracellular matrix production, were first described by Dr. Marshall Urist in 1965 [22], and are the most well-known and researched of the musculoskeletal growth factors. They also function in apoptosis [13] and reshaping the extracellular matrix. The membrane receptors and intracellular signaling mechanisms of these growth factors are well-defined [2]. Not only osteoblasts and chondrocytes but also osteoclasts [19] contain these membrane receptors, which indicates growth factors have a key role in the homeostasis of the musculoskeletal system. The externally administered local therapeutic quantity and duration that is required to trigger and/or control the event is, however, substantially higher than that of the endogenous dose. Responsive cells are essential at the administration site to have an optimal healing effect. BMP producing and marketing sources indicate that injecting or implanting these growth factors attracts stem cells. The mechanism of how BMPs work at atrophic nonunions where such cells are lacking needs further investigation. Recent preclinical and clinical studies including those published in this symposium will give insight into these mechanisms.There are several published clinical studies [9,14] with small sample size and a lack of control groups. In most of these studies the growth factor was combined with autografts or allografts. Are we willing to replace autografts and allografts with BMPs? Studies reporting complications of autografts and allografts suggest the answer is yes. BMPs may replace autografts when safety, efficacy and reliability studies are completed. Outcomes of other clinical studies [4,7,12] indicate BMP reduces blood loss between 43 to 336 ml and decreased operation time for 9 to 15 minutes. Although these findings are statistically significant, their clinical importance is open to discussion. The mechanism by which BMPs might reduce infection and improve disability, quality of life and pain scores needs to be explained. Do BMPs have complications? The answer is yes again. Increased numbers of inflammatory cells in sheep [6], increased serum antibody levels against BMPs, generalized edema, bone overgrowth and heterotopic ossification have recently been reported [20]. We must be aware of the side effects of musculoskeletal growth factors to use them safely. Indications of BMPs are expanding [1], however, clinical results on difficult healing fractures such as those of the scaphoid [3] and talus are infrequent. It is obvious that growth factors will find their deserved place in tissue engineering strategies in the near future [2]. Cells, carriers and growth factors are essential elements of this emerging technology. Appropriate carriers [16,21] of BMPs are still a focus of research. Today, nonviral delivery of the gene of the growth factor into...

Mechanistic, Mathematical Model to Predict the Dynamics of Tissue Genesis in Bone Defects via Mechanical Feedback and Mediation of Biochemical Factors

“…As BMPs are the most well-known and researched musculoskeletal growth factors [41] , they are the focus of the framework for growth factor activity in the model presented here (although future iterations of the model may be expanded to include an array of growth factors and cytokines that modulate tissue genesis and healing). BMPs are widely implicated as important regulatory factors during all stages of bone regeneration including cellular proliferation, differentiation, ECM production and apoptosis [42] .…”

Immunolocalization of bone morphogenetic protein 2 during the early healing events after guided bone regeneration

“…6 Bone morphogenetic proteins (BMPs), which regulate cellular proliferation, differentiation, and extracellular matrix production, were first described by Marshall Urist in 1965, 7 and are the best known and most researched of the musculoskeletal growth factors. 8 Bone morphogenetic protein 2 (BMP-2) plays an important role in the cascade of cellular events that regulate bone formation and repair, inducing the differentiation and proliferation of mesenchymal cells and the synthesis of extracellular matrix. [9][10][11][12][13] BMPs are able to induce the differentiation of undifferentiated cells around blood vessels into osteoblasts and chondrocytes and thus regulate bone formation.…”