Martina Pauk

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

PurposeThe purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.MethodsComplications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.ResultsClinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.ConclusionsCurrent issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.

Osteogrow: A Novel Bone Graft Substitute for Orthopedic Reconstruction

Complications associated with the clinical use of BMP2 and BMP7 result from the limited understanding of their molecular mechanisms in bone remodeling. Recently, a novel BMP6-based approach has been developed with superior healing results and reduced side effects in preclinical studies. BMP6-containing osteogenic medicinal product called Osteogrow, which is aimed to induce and accelerate bone formation, is currently being tested in clinical studies. It comprises of a biologically compatible autologous carrier made from the patient’s peripheral blood and of rhBMP6 as an active ingredient. Such formulation circumvents the use of animal-derived materials, significantly limits inflammatory processes common in commercial bone devices, and renders the carrier flexible and injectable ensuring the ease of use. The ongoing clinical trial results will provide a more detailed insight into the safety, tolerability, pharmacokinetics, and bone healing effects in humans and hopefully provide novel and valuable therapeutic options in the field of bone regeneration.

Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats

Abstract Liver fibrosis is a progressive pathological process resulting in an accumulation of excess extracellular matrix proteins. We discovered that bone morphogenetic protein 1-3 (BMP1-3), an isoform of the metalloproteinase Bmp1 gene, circulates in the plasma of healthy volunteers and its neutralization decreases the progression of chronic kidney disease in 5/6 nephrectomized rats. Here, we investigated the potential role of BMP1-3 in a chronic liver disease. Rats with carbon tetrachloride (CCl4)-induced liver fibrosis were treated with monoclonal anti-BMP1-3 antibodies. Treatment with anti-BMP1-3 antibodies dose-dependently lowered the amount of collagen type I, downregulated the expression of Tgfb1, Itgb6, Col1a1, and Acta2 and upregulated the expression of Ctgf, Itgb1, and Dcn. Mehanistically, BMP1-3 inhibition decreased the plasma levels of transforming growth factor beta 1(TGFβ1) by prevention of its activation and lowered the prodecorin production further suppressing the TGFβ1 profibrotic effect. Our results suggest that BMP1-3 inhibitors have significant potential for decreasing the progression of fibrosis in liver cirrhosis.

Elevated blood serotonin decreases bone volume via a mechanism involving insulin and calcitriol

To further characterize the role of serotonin (5HT) in bone metabolism, Wistar-Zagreb rat model consisting of the high-5HT and low-5HT subline with different platelet 5HT content and transporter (5HTT) activity has been used. Primary osteoclasts from the high-5HT subline had an increased expression of 5HTT, 5HT–2A receptor, Trap and cathepsin K, while osteoblasts showed no difference in the expression of 5HT elements or osteoblastic markers. However, upon addition of 5HT and insulin combination, expression of Alph and osteocalcin in osteoblasts was significantly upregulated. In 8 weeks old rats the bone volume of distal femur and lumbar spine was significantly decreased in high-5HT rats. Histomorphometric analysis revealed increased osteoblast activity in these animals, while no change in the number of bone cells was observed. Serum CTX value was significantly increased in high-5HT animals while no change in the osteocalcin level was detected. 5HT level had no effect on the PTH value, but calcitriol and FGF23 were decreased in high-5HT rats. Treatment with calcitriol reduced the platelet 5HT content by 20% in high-5HT rats while PTH had no effect on platelet 5HT content. High-5HT rats had a higher level of blood glucose and insulin, resulting in ahigher body mass as compared to low-5HT rats. A single streptozotocin injection lowered the insulin plasma value with a consequent decrease in the platelet 5HT by 20%. Treatment with fluvoxamine, a 5HTT inhibitor, reduced the 5HT level in both sublines by 50% that was accompanied by decreased insulin in plasma of low-5HT rats. These results demonstrate that 5HT affects the bone volume via a complex autocrine/paracrine and endocrine mechanism involving insulin and calcitriol. Thus, 5HT is not a single mediator of bone metabolism, but influences the bone volume via a complex biochemical network of hormones and growth factors associated with 5HT homeostasis.