Abstract
Introduction Heterotopic ossification (HO), also known as myositis ossification, paraosteoarthropathy, or heterotopic calcification, among others, is a common pathological condition that refers to ectopic bone formation in soft tissues. Although the molecular mechanism of HO is not fully understood, it is believed that signaling of bone morphogenetic proteins (BMPs) plays a key role in the overall process of HO. Today, recombinant human BMP-2 (rhBMP-2) and recombinant human BMP-7 (rhBMP-7) have been already actively used in clinical practice in the treatment of bone defects. However, despite the positive sides of using rhBMPs, there are a number of side effects, one of which is HO. Purpose In this study, we demonstrate cases of HO following the use of rhBMPs in both clinical and preclinical studies and make an attempt to explain the relationship between the signaling pathways of BMPs and the HO process, as well as the possibilities of preventing and treating the HO process. Materials and methods PubMed, Embase, the Cochrane Database, and Google Scholar were comprehensively searched for original articles, literature reviews, case reports, and meta-analyses demonstrating a causal relationship between therapeutic rhBMPs and HO as a complication. Results This review analyzes the potential for therapeutic use of rhBMPs in neurosurgery and traumatology and orthopedics, demonstrated by both clinical and preclinical studies. In particular, the studies confirm that ectopic bone formation is one of the side effects following administration of rhBMPs. Moreover, the molecular mechanisms of the HO process were highlighted, and the possibilities of modern methods of prevention and treatment of HO were discussed. Conclusion According to the FDA safety database for rhBMPs, the rates of adverse effects related to HO range from 1 % to 10 %. However, to date, the clinical use of rhBMPs is justified, especially when there are no alternative substitutes for bone grafting.
Highlights
Heterotopic ossification (HO), known as myositis ossification, paraosteoarthropathy, or heterotopic calcification, among others, is a common pathological condition that refers to ectopic bone formation in soft tissues
The studies demonstrate that endothelial cells (ECs), mesenchymal stem cells (MSCs), and pericytes that are present in striated muscle, tendons, and connective tissue, or even circulating stem/progenitor cells may be a source of HO development [1, 2 ]
It is well known that progenitor cell differentiation along the chondrogenic pathway and endochondral ossification is facilitated by various factors, including bone morphogenetic proteins (BMPs) signaling and transcription factors [8]
Summary
Heterotopic ossification (HO), known as myositis ossification, paraosteoarthropathy, or heterotopic calcification, among others, is a common pathological condition that refers to ectopic bone formation in soft tissues. Purpose In this study, we demonstrate cases of HO following the use of rhBMPs in both clinical and preclinical studies and make an attempt to explain the relationship between the signaling pathways of BMPs and the HO process, as well as the possibilities of preventing and treating the HO process. Recent in vitro and in vivo studies have proven the role of immune system cells, especially monocytes/macrophages, in the early HO stages [2, 3]. Those studies support the importance of monocytes/macrophages in the induction of neurogenic and genetic HO types. The presence of the cells reflects increased secretion of growth factors, cytokines/chemokines that stimulate HO, such as interleukins (IL-6 and IL-10), transforming growth factor beta-1 (TGF-β1), neurotrophin 3 (NT3), and bone morphogenetic proteins (BMPs) (BMP-2, 4 and 7) [4, 5]
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