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Bone Growth Factors

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Topic updated on 07/25/16 9:31am
 
Overview of Growth Factors
Factor Source Receptor Class Function
TGF-B Platelets, bone ECM, cartilage matrix
Seronine threonine sulfate Pleiotropic growth factor stimulates undifferentiated mensenchymal cell proliferation .
BMP Osteoprogenitor cells, osteoblasts, bone ECM
Seronine threonine sulfate Promotes differentiation of mesenchymal cells into chondrocytes and osteoblasts.
Promotes differentiation of osteoprogenitors into osteoblasts, influences skeletal pattern formation.
FGF Macrophages, mesenchymal cells, chondrocytes, osteoblasts Tyrosine kinase Mitogenic for mesenchymal cells, chondrocytes, and osteoblasts.
IGF Bone matrix, osteoblasts, chondrocytes Tyrosine kinase Promotes proliferation and differentiation of osteoprogenitor cells.
PDGF Platelets, osteoblasts Tyrosine kinase Mitogen for mesenchymal cells and osteoblasts; macrophage chemotaxis.
 
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  
  • Mechanism
    • osteoinductive
      • leads to bone formation
      • activates mesenchymal cells to transform into osteoblasts and produce bone
  • Signaling Pathways and Cellular Targets
    • BMP targets undifferentiated perivascular mesenchymal cells
    • activates a transmembrane serine/threonine kinase receptor that leads to the activation of intracellular signaling molecules called SMADs.
      • SMADS are primary intracellular signaling mediators
      • currently eight known SMADs, and the activation of different SMADs within a cell leads to different cellular responses.
  • Clinical applications
    • FDA-approved uses   
      • rhBMP-2  
        • single-­level ALIF from L2 to ­S1 levels in degenerative disc disease together with the lumbar tapered fusion device (LT Cage; Medtronic)
        • open tibial shaft fractures stabilized with an IM nail and treated within 14 days of the initial injury
      • rhBMP-7
        • as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed
        • as an alternative to autograft in compromised patients (with osteoporosis, smoking or diabetes) requiring revision posterolateral/intertransverse lumbar fusion for whom autologous bone and bone marrow harvest are not feasible or are not expected to promote fusion
    • contraindications
      • pregnancy
      • allergy to bovine type I collagen or recombinant human rhBMP­-2
      • infection
      • tumor
      • skeletal immaturity
Transforming Growth Factor-B (TGF-B)
  • Mechanism
    • secreted in a paracrine fashion
    • both osteoblast and osteoclasts synthesize and respond to TGF-B
    • found in fracture hematomas and believed to regulate cartilage and bone formation in fracture callus
    • stimulates production of Type II collagen and proteoglycans by mesenchymal cells.
    • induces osteoblasts to synthesize collagen
  • Signal Pathway & Cellular Targets
    • signal mechanism involves transmembrane serine/threonine kinase receptors
  • Clinical applications
    • TGF-B is used to coat porous coated implants to promote bone ingrowth
Insulin-like Growth Factor 1 (IGF-1)
  • Overview
    • IGF-1, formerly known as somatomedin-C, possibly acts by both paracrine and endocrine hormone pathways
    • most abundant growth factor in bone
  • Mechanism
    • the products of the GH-IGF-1 system induce proliferation without maturation of the growth plate and thus induce linear skeletal growth. 
    • the action of the thyroid hormone axis is via an active metabolite that enters target cells and signals a nuclear receptor to stimulate both proliferation and maturation of the growth plate. Increased amounts of the active steroid hormone metabolite promote proliferation and maturation of the growth plate
    • IGF-1 may have a role in enhancing bone formation in defects that heal via intramembranous ossification
  • Signal Pathway & Cellular Targets
    • signal mechanism involves tyrosine kinase receptors
Insulin-like Growth Factor 2 (IGF-2)
  • Overview
    • more potent than IGF-1
  • Mechanism
    • stimulates type I collagen production
    • stimulates cartilage matrix synthesis
    • stimulates cellular proliferation
    • stimulates bone formation
  • Signal Pathway & Cellular Targets
    • signal mechanism involves tyrosine kinase receptors
Fibroblast Growth Factor (FGF)
  • Overview
    • FGF-1 and FGF-2 are most abundant
    • promote growth and differentiation of a variety of cells
      • epithelial cells
      • myocytes
      • osteoblasts
      • chondrocytes
  • Mechanism
    • binds to membrane spanning tyrosine kinase
    • associated with angiogenesis and chondrocyte and osteoblast activation
    • involved in early stages of fracture healing
Platelet-derived growth factor (PDGF)
  • Mechanism
    • released from platelets and signals inflammatory cells to migrate to fracture site
    • role in fracture healing and bone repair has not been clearly defined
  • Signal Pathway & Cellular Targets
    • signal mechanism involves tyrosine kinase receptors

 

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Qbank (5 Questions)

TAG
(OBQ11.183) Altered BMP-4 signal transduction is known to be associated with which of the following diseases? Topic Review Topic

1. Fibrodysplasia ossificans progressiva
2. Mazabraud's syndrome
3. Ollier's syndrome
4. Osteopetrosis
5. Osteopoikilosis

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TAG
(OBQ09.139) All of the following are true of BMP-3 EXCEPT? Topic Review Topic

1. It antagonizes the activity of BMP-2
2. It is the most abundant BMP in demineralized bone matrix
3. Knockout mice have twice as much trabecular bone as controls
4. It is osteoinductive
5. It increases levels of chondrogenic markers like Type II collagen and aggregcan

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