Osteogenic Growth Factors and Cytokines and Their Role in Bone Repair Louis C

2. Osteogenic Growth Factors and Cytokines and Their Role in Bone Repair Louis C. Gerstenfeld, Cory M. Edgar, Sanjeev Kakar, Kimberly A. Jacobsen, and Thomas A. Einhorn transforming growth factor β (TGF-β) super- 2.1 Introduction family, angiogenic factors, and parathyroid hormone/parathyroid hormone-related peptide Ontogenetic development is initiated at the (PTH/PTHrP). Major emphasis has been time of fertilization and terminates with the directed to these molecules because their activ- differentiation, growth, and maturation of spe- ities constitute current targets of pharmaco- cialized tissues and organs. These developmen- logical studies to promote or alter bone healing. tal processes are characterized by molecular Short reviews of the fi broblast growth factor specialization that accompanies cellular differ- (FGF) and Wnt families of factors are also pre- entiation and tissue morphogenesis. Most sented in the context of their known functions developmental processes terminate after birth in skeletal development and intended use as or when animals reach sexual maturity, but therapeutic agents. The second half of the some morphogenetic processes are reinitiated review (sections 2.3–5) is focused on the in response to injury in specifi c tissues. One anatomy and cell biology of bone healing, on such regenerative process is the repair of skel- what is known about the temporal and spatial etal fractures and bone tissue after surgery, expression of the various cytokines during a process that recapitulates specifi c aspects bone healing, and how cytokines and morpho- of the initial developmental processes in the gens may therapeutically modify the repair course of healing [58, 209]. Several aspects of process. the postnatal tissue environment of fracture healing, however, are unique and differ from what occurs in embryological and postnatal 2.2 Cytokines, Morphogens, development. Understanding how cytokines and morphogens affect fracture or postsurgical and Growth Factors: healing is essential to the development of The TNF-a Family pharmacological and molecular approaches intended to enhance bone healing after surgery or traumatic injury, as well as to promote skel- 2.2.1 The TNF Family of Cytokines etal tissue engineering. and Their Intracellular Functions The fi rst half of this review (Section 2.2) will focus on several groups of soluble protein TNF was fi rst identifi ed in the early 1980s, and factors that regulate postnatal bone repair: the a large superfamily of related molecules has tumor necrosis factor α (TNF-α) family, the since been identifi ed. So far, 18 members with 17 18 Engineering of Functional Skeletal Tissues 15% to 25% amino acid sequence homology growth, primarily through the activation of the and at least six cell-surface receptors have been nuclear factor κB (NFκB) and c-Jun N-terminal described. The two members of this cytokine kinase (JNK) transcription factors. The dichot- family that have been the most extensively omy of cellular responses to these cytokines characterized are TNF and Fas ligand (FasL). resides in the receptors that are activated and The ligands of this family are all predominantly the downstream signal transduction molecules type II transmembrane proteins. The receptors that interact with these receptors. Signal trans- are all type I transmembrane proteins and are duction is mediated through a two-part system believed to aggregate upon interaction with of docking proteins including MORT/FADD, their ligands. Although the extracellular side TRADD, RIP, and CRADD, which bind to the of the receptors is conserved and composed death domain (DD) of the receptors, and the of cysteine repeats, the cytoplasmic domains of adaptor proteins that have been named TRAFs. the receptors are different and mediate unique Downstream from the coupled responses to activities that lead to a multitude of biological TNFR1 and TNFR2 that mediate cell survival responses through variations in their coupled are the various mitogen-activated protein signal transduction processes. These cytokines (MAP)-related kinases. Downstream from the have been implicated in a wide variety of apoptotic activation of TNFR1 and FAS is the diseases, including tumorigenesis, septic shock, activation of specifi c proteases (caspases) [19, viral replication, bone resorption, rheumatoid 121, 153, 187]. There is a further bifurcation arthritis, diabetes, and other infl ammatory of the apoptotic cascade, with two separate diseases [19, 121, 153, 187]. Recently, several pathways that can mediate apoptosis: an intrin- therapeutic regimens have been approved that sic (mitochondria-dependent low caspase 8) antagonize TNF-α activity to treat a variety of pathway and an extrinsic (mitochondria- autoimmune diseases, including rheumatoid independent high caspase 8) pathway [185]. To arthritis and Crohn’s disease [163, 184]. Pre- understand the complex regulatory functions liminary studies have also examined whether within a tissue that are mediated through the these approaches can be used to impede the actions of the TNF cytokine family, it is neces- loosening of orthopedic prostheses [37]. sary to defi ne the ligands and to specify the The TNF family members with the most actions of specifi c receptors and the specifi c homogeneity are TNF-α, TNF-β (LT-α), and mechanisms of intracellular transduction LT-β. Both TNF-α ligands and TNF-β (LT-α) within that tissue. are homotrimers, whereas LT-β is a heterotri- mer of (LT-α)1(LT-β)2. There are three receptors in this family: TNFR1/p55/death receptor 1/ 2.2.1.1 TNF Cytokines as Arbitrators of the DR1, TNFR2 (p75), and LT-β receptor. Both Tissue Microenvironment by Selective TNF ligands bind both TNF receptors, but LT- Promotion of Cell Death or Survival β/TNF-α trimers only bind to the LT receptor. FasL is a unique family member and is solely The TNF family of cytokines plays a central recognized by its receptor, FAS/Apo1/DR2 [211]. role in the timing of the immune response, Most cells express TNF-α and its receptors, but namely, when to terminate activation of the the expression of TNF-β and its receptor innate infl ammatory response and initiate the appears to be restricted to T cells and natural acquired immune response, and when to termi- killer cells. TNFR1 (p55) is constitutively nate an innate or acquired response and initi- expressed by almost all cells, but TNFR2 (p75) ate local tissue repair and regeneration. Thus is strongly induced in immune and infl amma- both TNFR1 and Fas mediate activation- tory responses. FasL and Fas are also expressed induced cell death in macrophages, T cells, and by many cells but show unique expression B cells [99, 111, 187]. The pathological manifes- during many developmental processes, includ- tations of inappropriate control of the apop- ing the hypertrophy of chondrocytes [72, 174] totic processes in immune function are seen in and the regulation of immune cell differentia- mice that are defi cient in TNFR1, Fas, and FAS/ tion [17, 23, 55, 192]. TNF-α and related cyto- TNFR1. These animals exhibit more severe kines either mediate programmed cell death autoimmune disease and accelerated lym- (apoptosis) or facilitate cell survival and phoproliferation. These responses indicate that Osteogenic Growth Factors and Cytokines and Their Role in Bone Repair 19 whereas Fas and TNFR1 receptors both activate 126]. Treatment of human articular chondro- the apoptotic cascade and carry out compensa- cytes with FasL in vitro causes apoptosis. tory or redundant functions, each receptor Because the Fas system is present in growth- mediates a unique set of biological responses plate chondrocytes in vivo, it may play a role in [229]. Thus failure to initiate the programmed chondrocyte apoptosis during endochondral cell death of one or another population of development [6, 83]. In previous studies, carti- immune cells that mediate the transition of the lage cells within the fracture callus [224] have specifi c stages of an immune response leads to been shown to express Fas, and articular chon- a variety of systemic autoimmune pathologies drocytes will undergo programmed cell death [204]. In essence, these cytokines act as the in response to TNF-α [69]. The relationship central arbitrators of a tissue’s microenviron- between the apoptotic process and the normal ment during immune activation. They do so progression of endochondral development can by promoting the survival of one population be observed in pathological conditions such as of cells while causing another to undergo rickets, as well as in the numerous genetically apoptosis. engineered defects that affect growth-cartilage The TNF-α family of cytokines has been the development. The hallmark of almost all of primary focus of many immune function these defects is either a foreshortening or an studies, but the death receptor family also plays expansion of the growth plates. Two examples a pivotal regulatory role in many developmen- of factors causing an expansion of the growth tal processes [43]. It is interesting that during plate are vitamin D defi ciency in growing postnatal tissue repair and regeneration these animals and the genetically engineered abla- cytokines directly and indirectly regulate many tion of matrix metalloproteinase 9 (MMP-9) nonimmune cell types downstream from an [210]. Ablation of the PTHrP gene, on the other initial immune response [82]. The signaling hand, causes an osteochondrodysplasia, functions by immune cell cytokines during primarily manifested in an accelerated hyper- postnatal tissue repair derive from functions trophy and removal of the chondrocytes. A carried out during embryogenesis. Alterna- phenomenon common to these very different tively, these cells may initiate postnatal repair pathologies of the endochondral process is that or regenerative processes that replace mecha- in all three the timing or rate of chondrocyte nisms that functioned during embryological apoptosis has been altered. The consequence of development. TNF-α thus functions within an abnormally timed apoptosis is that the skeletal tissues either during the course of microenvironment of the endochondral tissue normal skeletal homeostasis or in response to is altered by retention or loss of the chondro- tissue injury [158].

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