Bone morphogenetic proteins (BMPs) is the generic name for a family of proteins that can form bone de novo, for which they are considered osteoinductive

1. Bone
Morphogenetic
Proteins
Dr. Sushmit Singh
Junior Resident
Dept. Of Orthopaedics
Dr D Y Patil Medical College, Nerul

2. Introduction
 Bone Morphogenetic Proteins (BMPs) are a group of molecules that work by inducing
the mesenchymal stem cells to differentiate into bone forming cell lines that
form new bone.
 BMPs are involved in many physiological and pathological processes such as
 inflammatory response,
 bone formation and resorption,
 growth signaling pathways,
 oncogenesis and immune response.
 The BMPs are also referred to as osteogenic proteins (OPs). The BMPs play critical
roles in regulating cell growth, differentiation, and apoptosis in a variety of cells
during development, including osteoblasts and chondrocytes.

3.  In 1965, Marshal Urist demonstrated the ability of crude bone extracts to induce new
bone in an ectopic site. He coined the term “bone morphogenetic protein” or “osteogenic
protein” for the active ingredient of this extract.
 BMPs are expressed in early stages of fracture repair.
 primary activators of differentiation in osteoprogenitor and mesenchymal cells destined
to become osteoblasts and chondrocytes

4. Structure
 BMPs constitute the largest part of the TGF-ß super family which also comprises
activins and inhibins.
 The TGF-ß superfamily is comprised of growth factors and differentiation factors
which have homology in their primary amino acid sequence.
 Currently there are 20 known BMPs.
 In the bone, BMPs are secreted by osteoprogenitor cells, osteoblasts and platelets.
 BMPs are synthesized as precursor proteins. Active BMP is released by proteolytic
removal of the signal peptide and pro-peptide. BMP-1 is a metalloproteinase and is
not a member of the TGF-ß superfamily.
 BMPs are highly conserved across animal species. The BMP-7 of humans and mouse
share a 98% similarity in their amino acid sequence.

5. OSSIFICATION
 Formation of bone (ossification) occurs by both intramembranous ossification and
endochondral ossification.
 The cellular events of both endochondral and intramembranous ossification involve the
mesenchymal stem cells (MSCs). MSCs may be bone marrow derived or periosteum
derived. MSCs are pluripotent progenitors that can differentiate into osteoblast, chondroblast
and other connective tissue cell lines.
 Differentiation of MSCs is regulated by signaling pathways and molecules such as bone
morphogenetic proteins (BMP), Wnt, Notch, Hedgehog, and Fibroblast growth factor (FGF).
 The cellular and molecular events that govern the bone formation during development and
fracture healing are similar.
 The process of fracture healing is similar to endochondral ossification.
 In some situations, the process of fracture healing may fail, leading to nonunion or delayed
union. Such conditions as well as traumatic bone loss and spinal fusion surgery need
stimulation of the process of bone formation. This can be achieved by biophysical methods
such as ultrasound or biological interventions such as bone graft, bone marrow or
biologically active molecules.

7.  Autogenous bone graft is capable of stimulation of bone formation by the process of
osteogenesis, osteoconduction and osteoinduction.
 Autogenous iliac crest bone graft (AICBG) is considered the gold standard for stimulation of
bone formation in the treatment of bone defects and nonunions. However, limited availability
of bone graft, morbidity of graft harvest, and the variable success rate of union highlights
the need for a better option.
 One of the solutions to avoid the problems of autologous bone graft is the use of the BMPs as
a bone graft substitutes as they are capable of osteoinduction. It was hoped that equal or
better results can be achieved without the morbidity of graft harvest.

8. FUNCTIONS
 The actions of BMPs depend on the target cell type, the maturation phase of target cells, local
concentration of BMPs and other biological signals.
 BMPs are mitogens (growth factors) that stimulate the multiplication of connective tissue cells
as well as morphogens (differentiation factors) that transform connective tissue cells into
osteoprogenitor cells.
 They serve in signal pathways that influence cell division, matrix synthesis and tissue
differentiation. They play a pivotal role in embryonic development.
 BMPs induce bone through intramembranous ossification or endochondral ossification. They
induce osteoclasts as well leading to bone resorption.
 BMP receptors are transmembranous cell surface receptors. The receptors are made up of Type I
and Type II serine/threonine kinase proteins that leads to the activation of intracellular signaling
molecules called SMADs
 Once phosphorylated, the Smads 1, 5, and 8 bind to co-Smads and Smad 4 and translocate
into the cell nucleus and results in the activation of transcriptional factors for the BMP
response genes.
 The local effects of BMP is regulated by a number of extra cellular and intracellular antagonists.
Known extracellular antagonists are noggin, chordin. Known intracellular antagonists are
Smad6, Smad7, Smad8b, Smurf1 and Smurf2. They either interfere with the activation of R-
Smads or facilitate their degradation.

10.  Bone Morphogenetic Protein (BMP) & SMADs
 Overview
 BMPs belong to the TGF-B superfamily
 BMP 2,4,6, and 7 all exhibit osteoinductive activity
 BMP 3 does not exhibit osteoinductive activity
 Mutations in BMP-4 are associated with Fibrodysplasia ossificans
progressiva.

11.  Altered BMP-4 signal transduction is known to be
associated with Fibrodysplasia ossificans progressiva

12.  Bone morphogenetic protein is a water-soluble, low-molecular weight protein which diffuses
easily in the body fluids. If administered alone, the protein will lost rapidly due to diffusion or
irrigation.
 Hence BMP is administered in a carrier to have a prolonged localized effect at the bone healing
site. The BMP carriers can be broadly classified into inorganic salts, naturally occurring polymeric
substances, synthetic polymers, and composites of synthetic and naturally occurring polymers.
 Collagen is the most commonly used carrier, and Type I collagen is preferred. It may be
sourced from bone or tendons. BMP binds tightly to collagen extracted from bone and less
tightly to collagen extracted from tendons.
 Compression of the collagen carrier leads to rapid diffusion of BMPs; hence it should be
protected by a cage. If collagen extracted from bone is used, it need not be protected by cage
as it tightly binds to BMP.

13. USE
 BMPs were available for use from 2002 onwards
 The estimated risk of rhBMP-2 use as per these clinical trials could be calculated to be less
than 0.5% with 99% certainty which was 40 times lower than common analgesics and
antibiotics
 The two forms of Recombinant human bone morphogenetic protein (rhBMP) are rhBMP2
and rhBMP7. rhBMP 7 is also known as osteogenic Protein 1 (OP 1).
 BMPs are being used in fresh open fractures of tibia and tibial non unions
 Use in fresh fractures have found to have decreased rates of infection partly due to increase
stability imparted.
 rhBMP2 and 7 has been approved by FDA for use in lumbar interbody spinal fusion cages
in US.
 The primary goals of using BMP in spinal fusions are:
To create a spinal fusion as well as or better than using the patient’s own bone.
To eliminate the need for harvesting the patient's bone from his or her hip, thus
avoiding the potential side effects and complications of the bone harvesting procedure

14. Disadvantages
 Several independent studies started reporting serious complications with rhBMP-2 use started
appearing from 2006 onwards
 These complications included
 increased postoperative pain and radiculitis,
 increased infection rates,
 Increased postoperative swelling,
 increased risk of spinal canal heterotopic ossification and
 increased risk of malignancy.
 Patients given BMPs had greater incidence of back and leg pain in the early postoperative
period possibly due to proinflammatory effects of BMP.
 The rate of epidural hematoma and wound complications with rhBMP-2 was 5 times higher
when compared to AICBG.

15.  BMP has widespread biological effects; many unknown or not clearly understood. Even though
BMP is a human protein, it may induce an allergic response.
 Some spontaneously evolving osteosarcomas contain high levels of BMPs and hence the
cancer risk is a concern.
 BMP is a morphogen as well as a mitogen hence risk of cancer is possible
 Uncontrollable bone growth into the spinal canal or intervertebral foramen is a known
complication of clinical use of BMP. Revision surgery with excision of heterotopic ossification
in the spinal canal and/or intervertebral foramen is a difficult task with unpredictable results.
 BMP has only been approved for one type of spinal fusion, anterior lumbar interbody
fusion
RECENT STUDIES AND UPDATES

16. CONCLUSION
 In spite of this debacle it remains a fact that BMPs are an important discovery
that have clinical applications. The ideal molecule or molecules, their dose, timing
and indications as well as contraindications need further refinement.
BMP is much more expensive (between 200%-500% more expensive) than other bone graft
substitutes.
It is not fully understood how BMP’s work or what other side effects they may produce. BMP-2
has received FDA approval for use in anterior lumbar interbody fusion in titanium cylindrical
cages (a form of cages that are not commonly used anymore).
The FDA recently released a cautionary letter recommending that BMP-2 not be used in
anterior cervical fusions as it can cause massive soft tissue swelling with postoperative
compromise and restriction of the patient’s airway.

17. THANK YOU