Костные морфогенетические белки: роль в развитии, патологиях и терапии.

Group of growth factor proteins
Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body. The important functioning of BMP signals in physiology is emphasized by the multitude of roles for dysregulated BMP signalling in pathological processes. Cancerous disease often involves misregulation of the BMP signalling system. Absence of BMP signalling is, for instance, an important factor in the progression of colon cancer, and conversely, overactivation of BMP signalling following reflux induced esophagitis provokes Barrett's esophagus and is thus instrumental in the development of esophageal adenocarcinoma. Recombinant human BMPs (rhBMPs) are used in orthopedic applications such as spinal fusions, nonunions, and oral surgery. rhBMP 2 and rhBMP 7 are Food and Drug Administration (FDA) approved for some uses. rhBMP 2 causes more overgrown bone than any other BMPs and is widely used off label.

BMPs for clinical use are produced using recombinant DNA technology (recombinant human BMPs; rhBMPs). Recombinant BMP 2 and BMP 7 are currently approved for human use. BMP 7 has also recently found use in the treatment of chronic kidney disease (CKD). BMP 7 has been shown in murine animal models to reverse the loss of glomeruli due to sclerosis. A 2022 study by researchers from the Mayo Clinic, Maastricht University, and Ethris GmBH, a biotech company that focuses on RNA therapeutics, found that chemically modified mRNA encoding BMP 2 promoted dosage dependent healing of femoral osteotomies in male rats. The mRNA molecules were complexed within nonviral lipid particles, loaded onto sponges, and surgically implanted into the bone defects. They remained localized around the site of application. Compared to receiving rhBMP 2 directly, bony tissues regenerated after mRNA treatment displayed superior strength and less formation of massive callus.

Although rhBMP 2 and rhBMP 7 are used in the treatment of a variety of bone related conditions including spinal fusions and nonunions, the risks of this off label treatment are not understood. While rhBMPs are approved for specific applications (spinal lumbar fusions with an anterior approach and tibia nonunions), up to 85% of all BMP usage is off label.

Bone morphogenetic protein (rhBMP) should not be routinely used in any type of anterior cervical spine fusion, such as with anterior cervical discectomy and fusion. There are reports of this therapy causing swelling of soft tissue which in turn can cause life threatening complications due to difficulty swallowing and pressure on the respiratory tract. As a member of the transforming growth factor beta superfamily, BMP signaling regulates a variety of embryonic patterning during fetal and embryonic development. For example, BMP signaling controls the early formation of the Müllerian duct (MD) which is a tubular structure in early embryonic developmental stage and eventually becomes female reproductive tracts. Chemical inhibiting BMP signals in chicken embryo caused a disruption of MD invagination and blocked the epithelial thickening of the MD forming region, indicating that the BMP signals play a role in early MD development. Moreover, BMP signaling is involved in the formation of foregut and hindgut, intestinal villus patterning, and endocardial differentiation. Villi contribute to increase the effective absorption of nutrients by extending the surface area in small intestine. Gain or lose function of BMP signaling altered the patterning of clusters and emergence of villi in mouse intestinal model. BMP signal derived from myocardium is also involved in endocardial differentiation during heart development. Inhibited BMP signal in zebrafish embryonic model caused strong reduction of endocardial differentiation, but only had little effect in myocardial development. In addition, Notch Wnt Bmp crosstalk is required for radial patterning during mouse cochlea development via antagonizing manner. Mutations in BMPs and their inhibitors are associated with a number of human disorders which affect the skeleton. Several BMPs are also named 'cartilage derived morphogenetic proteins' (CDMPs), while others are referred to as 'growth differentiation factors' (GDFs). BMPs are also involved in adipogenesis and functional regulation of adipose tissue. BMP4 favors white adipogenesis, whereas BMP7 activates brown fat functionality; BMP inhibitors are also involved in this regulation The current nomenclature only recognizes 13, as many others are put under the growth differentiation factor naming instead. BMP Known functions Gene LocusBMP1*BMP1 does not belong to the TGF β family of proteins. It is a metalloprotease that acts on procollagen I, II, and III. It is involved in cartilage development. Chromosome: 8; Location: 8p21BMP2 Acts as a disulfide linked homodimer and induces bone and cartilage formation. It is a candidate as a retinoid mediator. Plays a key role in osteoblast differentiation. Chromosome: 20; Location: 20p12BMP3 Induces bone formation. Chromosome: 14; Location: 14p22BMP4 Regulates the formation of teeth, limbs and bone from mesoderm. It also plays a role in fracture repair, epidermis formation, dorsal ventral axis formation, and ovarian follical development. Chromosome: 14; Location: 14q22 q23BMP5 Performs functions in cartilage development. Chromosome: 6; Location: 6p12.1BMP6 Plays a role in joint integrity in adults. Controls iron homeostasis via regulation of hepcidin. Chromosome: 6; Location: 6p12.1BMP7 Plays a key role in osteoblast differentiation. It also induces the production of SMAD1. Also key in renal development and repair. Chromosome: 20; Location: 20q13BMP8a Involved in bone and cartilage development. Chromosome: 1; Location: 1p35–p32BMP8b Expressed in the hippocampus. Chromosome: 1; Location: 1p35–p32BMP10 May play a role in the trabeculation of the embryonic heart. Chromosome: 2; Location: 2p14BMP11 Controls anterior posterior patterning. Chromosome: 12; Location: 12pBMP15 May play a role in oocyte and follicular development. Chromosome: X; Location: Xp11.2

From the time of Hippocrates it has been known that bone has considerable potential for regeneration and repair. Nicholas Senn, a surgeon at Rush Medical College in Chicago, described the utility of antiseptic decalcified bone implants in the treatment of osteomyelitis and certain bone deformities. Pierre Lacroix proposed that there might be a hypothetical substance, osteogenin, that might initiate bone growth. The biological basis of bone morphogenesis was shown by Marshall R. Urist. Urist made the key discovery that demineralized, lyophilized segments of bone induced new bone formation when implanted in muscle pouches in rabbits. This discovery was published in 1965 by Urist in Science. Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971. Bone induction is a sequential multistep cascade. The key steps in this cascade are chemotaxis, mitosis, and differentiation. Early studies by Hari Reddi unraveled the sequence of events involved in bone matrix induced bone morphogenesis. On the basis of the above work, it seemed likely that morphogens were present in the bone matrix. Using a battery of bioassays for bone formation, a systematic study was undertaken to isolate and purify putative bone morphogenetic proteins. A major stumbling block to purification was the insolubility of demineralized bone matrix. To overcome this hurdle, Hari Reddi and Kuber Sampath used dissociative extractants, such as 4M guanidine HCL, 8M urea, or 1% SDS. The soluble extract alone or the insoluble residues alone were incapable of new bone induction. This work suggested that the optimal osteogenic activity requires a synergy between soluble extract and the insoluble collagenous substratum. It not only represented a significant advance toward the final purification of bone morphogenetic proteins by the Reddi laboratory, but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.

At between US$6,000 and $10,000 for a typical treatment, BMPs can be costly compared with other techniques such as bone grafting. However, this cost is often far less than the costs required with orthopaedic revision in multiple surgeries. While there is little debate that rhBMPs are successful clinically, but some of the surgeons responsible for the original Medtronic supported studies on the efficacy of rhBMP 2 have been accused of bias and conflict of interest. For example, one surgeon, a lead author on four of these research papers, did not disclose any financial ties while with the company on three of the papers; he was paid over $4 million by Medtronic. It has since been revealed that potential complications can arise from the use including implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation.