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