Bone Growth Factors - Basic Science

                        SUMMARY
                    
                        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
    
    has been found to increase chondrogenic phenotype and matrix synthesis in intervertebral discs
- 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

Peroxisome proliferator-activated receptor gamma (PPAR-gamma or PPARG)
- Overview
  - key factor demonstrated in adipogenic differentiation of mesenchymal precursor cells in vitro
- Signal Pathway & Cellular Targets
  - a nuclear binding receptor that binds to DNA and regulates transcription of target genes
- Clinical and research applications
  - utilized for adipogenic differentiation in vitro
  - agonists are being utilized to attempt treatment of hyperglycemia and hyperlipidemia
  - targeted by thiazolidinediones for treatment of diabetes

Action	Numeric Key	Letter Key	Function Key
Show Bullets		S	Enter (frontside only)
20%	1	N
40%	2	H
60%	3	F	Enter (backside only)
80%	4	E
100%	5	M
Toss	0	T

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.