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Bone morphogenic proteins seminar


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Bone morphogenic proteins seminar.

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Bone morphogenic proteins seminar

  2. 2. INTRODUCTION  The bone morphogenic proteins are a group of related proteins that are found in the body and are important for skeletal development.  Extracellular matrix(ECM) contains ‘morphogenetic factors’ apart from growth factors which are capable of inducing de-novo bone formation.  Inductive interactions between these morphogenetic proteins and target cell leads to sequential biochemical and morphogenetic events resulting in differentiation of endochondral bone.
  3. 3.  Bone Morphogenetic Proteins (BMPs) were acknowledged to the world when Marshall Urist implanted demineralized bone matrix intra muscularly into the rodents and observed new bone formation.  Urist named them ‘bone morphogenetic proteins’ believing that they are capable of determining morphogenesis of structures such as bone.  Subsequently he was able to isolate the protein responsible for inducing new bone formation.
  4. 4.  BMPs, composed of 400-525 amino acids, comprise one subset of the transforming growth factor-B superfamily  BMPs stimulate proliferation and migration of undifferentiated bone cell precursors with little or no effect on mature osteoprogenitor cells  Thus, the main action of BMPs is to commit undifferentiated puripotential cells to differentiate in to cartilage and bone forming cells  BMPs are abundant in bone and are produced by several cell types including osteoblasts
  5. 5. HISTORICAL BACKGROUND  In 1889 Senn first found that decalcified ox bone promoted healing of osteomyelitic defects  He proposed that there was something in decalcified bone that was responsible for bone formation  In 1938 Lavender implanted living bone fragments 1-1.5cm in length either subcutaneously or intramuscularly
  6. 6.  These fragments were first treated by scraping away the periosteum, and in some specimens, a superficial layer of bone was also removed  Upon obtaining regenerated bone, he was able to show that it was neither the periosteum nor the cells on the surface or within the graft was responsible for new bone growth  He proposed that there must be something which originated from the graft itself, possibly a substance which was soluble in the lymph tissue
  7. 7.  In early 1960s several resarchers were investigating the process of calcification  In a series of experiments designed to test the triphasic theory of calcification, Urist et al discovered that control samples of untreated, decalcified bone implanted into muscle pouches of rabbits and rats resulted in new cartilage and bone formation by auto-induction
  8. 8.  The purification of BMPs was completed using the rat ectopic bone formation assay  This assay involves combining the sample containing the unknown protein to be assayed with demineralized rat bone matrix, which has been treated with dissociative agents such as guanidine and urea to remove all of the endogenous BMP activity
  9. 9.  This combination is then implanted subcutaneously in rats, and after 1-2 weeks, formation of new cartilage and bone is detected histologically  Using this bioassay, BMPs were purified and sequenced  Johnson et al in 1992 successfully purified human bone morphogenic proteins  13 BMP sequences have been cloned so far
  10. 10. PROPERTIES OF BONE MORPHOGENIC PROTEINS  They act as mitogens on undifferentiated mesenchymal cells and osteoblast precursors  Structurally they are related members of TGF-B superfamily  BMP 2-12 singly initiate de novo endochondral bone formation  BMPs induce bone formation where as other growth factors such as TGF-B1 or PDGF do not
  11. 11.  BMPs have an anabolic effect on periodontal tissues through stimulation of osteoblastic differentiation in human periodontal ligament cells  Bone allograft materials contain varying amount of BMPs, such as BMP-2,4 and -7 . A deficiency of BMP like proteins retards bone cell differentiation and may account for a failure of fracture to heal  Recombinant BMP’s (rh BMP’s) have been shown to promote bone formation
  12. 12.  They induce the expression of osteoblast phenotype ( ie. Increase in alkaline phosphatase activity in bone cells)  Act as chemoattractants for mesenchymal cells and monocytes as well as binding to extracellular matrix type IV collagen
  13. 13. Role of BMPs IN PERIODONTAL REGENERATION  BMPs have been used extensively by researchers to induce periodontal tissue regeneration in a variety of animal models as well as in human studies with varying degrees of success  Researchers have proposed that BMPs possess a structure/activity profile with BMP-2 exhibiting mainly osteogenic properties while oseteogenic protein-1 (OP-1), also known as BMP-7, was mainly cementogenic in its activities
  14. 14.  Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been used to investigate periodontal regeneration  Researchers successfully achieved periodontal regeneration in dogs using recombinant human bone morphogenetic protein-2(rhBMP-2) and a synthetic carrier  Clinical trials using rhBMP-2 in an absorbable collagen sponge carrier have yielded encouraging results with the protein and carrier being well tolerated locally and systemically.
  15. 15. STRUCTURE OF BMPs  There are about 20 BMPs identified till now  They belong to Transforming Growth Factor B superfamily except BMP1 which is a metalloproteinase  The basic structure of a BMP protein has: Hydrophobic secretory leader sequence Large propeptide region, and Mature of domain
  16. 16.  BMPs are divided into 3 groups: BMP-2 and BMP-4 has similar seven-cysteine domains but varies in amino terminal regions- share 92% of homology BMP-5, BMP-6, BMP-7, BMP-8 share sequence homology BMP-7 is OP-1 osteoprotegrin 1 and BMP-8 is OP-1 osteoprotegrin 2 BMP-3(osteogenin), differs from these two subgroups, form a different entity
  17. 17.  Recombinant human BMP-2 (rhBMP-2) has been produced using a Chinese hamster ovary (CHO) cell expression system rhBMP-2 causes bone formation by intramembranous as well as the endochondral method. Other BMPs, including BMP-4, BMP-5, BMP-6 and BMP-7, also induce bone in a similar manner although there could be variation in the amount and rate of bone and cartilage formation
  19. 19. BMP SIGNALLING SYSTEM  BMPs signal through serine/threonine kinase receptors that are composed of type I and type II subtypes  Three type I receptors have been shown to bind BMP ligands, including type IA and type IB BMP receptors [BMPR IA(ALK-3) and BMPR-IB(ALK-6)] and type IA activin receptor (Act RIA or ALK-2)
  20. 20.  The type I BMP receptor substrates include the Smad proteins, which play a central role in the relay of BMP signals from the receptor to target genes in the nucleus.  Smad1, Smad5 and Smad8 are phosphorylated by BMP receptors in a ligand dependent manner  After release from the receptor, Smad proteins associate with the related protein Smad4, which acts as a shared partner  This complex translocates into the nucleus and participates in gene transcription with other transcription factors
  21. 21. BRIEF DESCRIPTION OF SOME WELL INVESTIGATED BMPs  BMP1: Genes for BMP1 are located on chromosome 8 It does not belong to the TGF-B family of proteins It is a metalloprotease that acts on procollagen I, II, III It is involved in cartilage development BMP2: It is a major inducer of osteoblast differentiation The genes are located on chromosome 20
  22. 22.  BMP 3: Induces bone formation The genes are located on chromosome 14 BMP 4: Regulates the formation of teeth, limbs and bone from mesoderm It also plays a role in fracture repair Genes are located on chromosome 14
  23. 23.  BMP 5 : Performs functions in cartilage development Genes are located on chromosome 6 BMP 6: Plays a role in joint integrity in adults Genes are located on chromosome 6 BMP 7: Plays a key role in osteoblast differentiation It also induces the production of SMAD1 Also key in renal development and repair Genes are located on chromosome 20 It is also known as osteogenic protein-1
  24. 24. ROLE OF BMPs in EMBRYO DEVELOPMENT  The bone inducing property of BMPs in extra skeletal tissues gives clue regarding their involvement in embryonic development and also in post natal bone differentiation (RIPOMANTI 1992)  BMP2 was localised in mouse embryo at condensing precartilagenous mesenchyme, and in developing bones thus indicating it could also regulate cartilage and bone formation
  25. 25.  Osteogenin was also observed in rat embryo  BMP 2A was found localized in developing mouse hair follicles, limb buds, tooth buds – including the dental papilla and the odontoblastic layer, and in the mesenchyme of craniofacial region including Meckel’s and nasal cartilage and that of the palatal shelves  Thus BMPs are believed to regulate embryogenesis
  26. 26. CLINICAL APPLICATIONS  BMPs are of tremendous interest as therapeutic agents for healing bone fractures, including non union and in open tibial fracture  Also used in spinal fusion and reported to prevent osteoporosis  In dentistry, it is used for augmentation of maxillary sinus floor and alveolar ridge
  27. 27.  BMPs may provide a promising alternative to traditional grafting procedures  Its scope further extends in treating periodontal bone defects and in implant placement along with alloplastic materials, root coverage procedures and in periodontal regeneration  The combination of BMP2/ACS is commercially available as INFUSEVR bone graft (Medtronic, Minneapolis, MN), is useful for sinus lifting and implant dentistry  Potential of BMP-2 helps in regenerating bone in irradiated tissues seems promising in rehabilitating patients who have undergone radiation therapy and need bone reconstruction
  28. 28. BMPs in TISSUE ENGINEERING  Tissue engineering aims to reconstruct lost tissues or organs and is considered as the ultimate regenerative technique  Using tissue engineering, unwanted reaction which arise due to grafts such as tissue biocompatibility or rejection could be avoided  With the help of tissue engineering, therapies such as the production of skin to treat burns, bone grafts, arteries to treat atherosclerotic vascular disease and cartilage for plastic and reconstructive surgeries have been achieved
  29. 29.  Tissue engineering is being applied in dentistry for the regeneration of temporomandibular joint, periodontal ligament, dentin, enamel, pulp and integrated tooth tissues  Tissue engineering has three key features namely: Cells Scaffolds Signaling molecules such as growth factors
  30. 30.  Cells synthesise the matrix essential for the new tissue  Scaffolds provide the environment for the cells to synthesise matrix  Growth factors facilitate and promote this action  The growth factors that have been frequently applied to tissue engineering include bone morphogenetic proteins(BMP), basic fibroblast growth factor, vascular epithelial growth factor and transforming growth factor-B
  31. 31.  The BMP/TGF-b signalling pathway mediates osteoblastic differentiation and in vivo bone formation; BMP-2 and -7 were reported to play a role in the differentiation of periodontal ligament stem cells(PDLSC) and dental follicle stem cells  Reparative dentin formation was promoted by BMP-2 and -7.
  32. 32. BMPs in SOCKET AUGMENTATION  BMPs when used in augmentation of socket and maxillary sinus wall were found to : promote soft tissue healing minimize surgery time reduce potential post surgical infection accelerate cell migration promotes early bone formation
  33. 33. BMPs in IMPLANTOLOGY  Application of BMPs for the osseointegration of endosseous implant has been evaluated by some authors  Osseointegration is critical for endosseous implant in which there is complete union of implant with bone  Sometimes there would be insufficiency in quality or amount of bone, which is addressed by using grafts or growth factors
  34. 34.  In human trial studies conducted by Howell in 1997 and Cochran et al in 2000 using recombinant human BMP-2 in collagen sponge carrier, bone formation at the extracted site was observed, which helped in endosseous implant placement  Boyne et al in 1997, observed bone formation in sinus lift procedure using the same combination and this aided in implant placement (Boyne PJ)
  35. 35. LIMITATIONS  Though BMPs are potential candidates for promotion of regeneration of periodontium, limitations do exist  Ankylosis of varying degrees has been observed in some studies  Still there are difficulties in the method of delivering BMPs to the target site to achieve a constant supply of BMPs  Thus gene therapy and other modes of targeted delivery are being developed. BMPs are also associated with some systemic toxicity
  36. 36. CONCLUSION  BMPs apart from inducing new bone also seem applicable in multiple modes of regeneration like being used along with implants  Though the discovery and usage of BMPs are like the ‘light at the end of tunnel’ towards periodontal regeneration, more experimental studies and research are needed to fully tap their potential for regeneration