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BONE MORPHOGENIC PROTEINS (BMPs) - In bone and cartilage healing and osteosarcoma 

First broadcast on www.provet.co.uk 


This information is provided by Provet for educational purposes only.

You should seek the advice of your veterinarian if your pet is ill as only he or she can correctly advise on the diagnosis and recommend the treatment that is most appropriate for your pet.

Bone Morphogenic Proteins (BMPs) applications in canine orthopaedics ?

There are many exciting new developments in the field of bone healing and none more so than the work being done on stem cells and Bone Morphogenic Proteins (BMPs). BMPs  are unique substances that can induce the complete cycle of endochondral ossification including the conversion of undifferentiated mesenchymal cells into both chondroblasts and osteoblasts. In addition these substances instruct the osteoblasts on where to lay down bone, and so they are important in embryological development as well as bone repair. In the tragic genetic disease in humans known as fibrodysplasia ossificans progressiva  BMP-4 is known to be released at points of trauma from white cells which migrate into the area.  In humans  BMPs are being used in clinical trials with patients that have non-healing fractures. In studies conducted in dogs these substances have been shown to significantly improve fracture healing and they may be very useful in the management of fractures in the future. 

In dogs the beneficial effects have been recognised since the 1980's : 

1985 Jul-Aug;(197):301-11.

Induced regeneration of calvaria by bone morphogenetic protein (BMP) in dogs.

Sato K, Urist MR.

Abstract

In the adult dog, a 14-mm skull trephine defect regenerates only incompletely in the lifetime of the individual. Only about half of the defect is repaired; the regenerated part develops by extension of growth from the bony rim. Correlated roentgenographic and histomorphometric methods demonstrate that new bone develops by proliferation of preexisting osteoprogenitor cells lining the diploë and perivascular cells of the bone marrow stroma. An autogeneic bone graft, including bone marrow, provides a supplementary supply of cells in a homostructural framework and generally completes the repair process. Transplants of bone marrow alone fail to repair the defect. Implants of bovine bone morphogenetic protein (bBMP) and a carrier consisting of matrix gamma-carboxyglutamic acid rich protein (without any additional bone or bone marrow) induce repair almost as completely as an autograft. BMP-induced bone regeneration is incomplete in the thin lateral temporal marrow-deficient part of the cranium. Implants of BMP plus bone marrow induce complete repair, suggesting that calvarial bone regeneration is bone marrow stroma-dependent for a supply of target cells. The target for BMP in cranial bone regeneration is the perivascular connective tissue cells (pericyte) of the host bed marrow stroma and endosteum. The molecular mechanism of differentiation of pericytes into osteoprogenitor cells is not known, but the process is irreversible, heritable, and presents a solvable problem.

Subsequent studies showed beneficial effects in cartilage repair :

Int Orthop. 2007 Dec;31(6):773-81. Epub 2007 Aug 9.

OP-1/BMP-7 in cartilage repair.

Chubinskaya S, Hurtig M, Rueger DC.

Source

Department of Biochemistry, Orthopedics and Section of Rheumatology (Department of Internal Medicine), Rush University Medical Center, Chicago, IL, 60612, USA.

Abstract

Three years ago we published a book chapter on the role of bone morphogenetic proteins (BMPs) in cartilage repair. Since that time our understanding of the function of osteogenic protein-1 (OP-1) or BMP-7 in cartilage homeostasis and repair has substantially improved and therefore we decided to devote a current review solely to this BMP. Here we summarise the information accumulated on OP-1 from in vitro and ex vivo studies with cartilage cells and tissues as well as from in vivo studies of cartilage repair in various animal models. The primary focus is on articular chondrocytes and cartilage, but data will also be presented on nonarticular cartilage, particularly from the intervertebral disc. The data show that OP-1 is a unique growth factor which, unlike other members of the same BMP family, exhibits in addition to its strong pro-anabolic activity very prominent anti-catabolic properties. Animal studies have demonstrated that OP-1 has the ability to repair cartilage in vivo in various models of articular cartilage degradation, including focal osteochondral and chondral defects and osteoarthritis, as well as models of degeneration in intervertebral disc cartilage. Together our findings indicate a significant promise for OP-1 as therapeutic in cartilage repair.

And more recently it has been demonstrated that there may be a role for BMPs in the management of canine osteosarcoma :

BMC Vet Res. 2012 Feb 22;8:17. doi: 10.1186/1746-6148-8-17.

Mesenchymal stem cells with rhBMP-2 inhibits the growth of canine osteosarcoma cells.

Rici RE, Alcântara D, Fratini P, Wenceslau CV, Ambrósio CE, Miglino MA, Maria DA.

Source

Department of Surgery, Faculty of the Veterinary Medicine and Zootecny, São Paulo University, São Paulo, Brazil. roseeli@usp.br

Abstract

BACKGROUND:

The bone morphogenetic proteins (BMPs) belong to a unique group of proteins that includes the growth factor TGF-β. BMPs play important roles in cell differentiation, cell proliferation, and inhibition of cell growth. They also participate in the maturation of several cell types, depending on the microenvironment and interactions with other regulatory factors. Depending on their concentration gradient, the BMPs can attract various types of cells and act as chemotactic, mitogenic, or differentiation agents. BMPs can interfere with cell proliferation and the formation of cartilage and bone. In addition, BMPs can induce the differentiation of mesenchymal progenitor cells into various cell types, including chondroblasts and osteoblasts. The aim of this study was to analyze the effects of treatment with rhBMP-2 on the proliferation of canine mesenchymal stem cells (cMSCs) and the tumor suppression properties of rhBMP-2 in canine osteocarcoma (OST) cells. Osteosarcoma cell lines were isolated from biopsies and excisions of animals with osteosarcoma and were characterized by the Laboratory of Biochemistry and Biophysics, Butantan Institute. The mesenchymal stem cells were derived from the bone marrow of canine fetuses (cMSCs) and belong to the University of São Paulo, College of Veterinary Medicine (FMVZ-USP) stem cell bank. After expansion, the cells were cultured in a 12-well Transwell system; cells were treated with bone marrow mesenchymal stem cells associated with rhBMP2. Expression of the intracytoplasmic and nuclear markers such as Caspase-3, Bax, Bad, Bcl-2, Ki-67, p53, Oct3/4, Nanog, Stro-1 were performed by flow citometry.

RESULTS:

We evaluated the regenerative potential of in vitro treatment with rhBMP-2 and found that both osteogenic induction and tumor regression occur in stem cells from canine bone marrow. rhBMP-2 inhibits the proliferation capacity of OST cells by mechanisms of apoptosis and tumor suppression mediated by p53.

CONCLUSION:

We propose that rhBMP-2 has great therapeutic potential in bone marrow cells by serving as a tumor suppressor to increase p53 and the pro-apoptotic proteins Bad and Bax, as well as by increasing the activity of phosphorylated caspase 3.

STUDY DESIGN:

Canine bone marrow mesenchymal stem cells associated with rhBMP2 in canine osteosarcoma treatment: "in vitro" study.

Updated January 2016