Growth factors and the regulation of bone remodeling. E Canalis, … , T McCarthy, M Centrella J Clin Invest. 1988;81(2):277-281. https://doi.org/10.1172/JCI113318. Research Article Find the latest version: https://jci.me/113318/pdf Perspectives Growth Factors and the Regulation of Bone Remodeling Ernesto Canalis, Thomas McCarthy, and Michael Centrella Department ofMedicine (Endocrine Section) and Research Laboratory, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105; and The University of Connecticut Health Center, Farmington, Connecticut 06032 Introduction (BDGF),1 insulin-like growth factor (IGF), or somatomedin Bone remodeling is a complex process regulated by hormones (Sm) C, and platelet-derived growth factor (2, 5-7). These fac- and growth factors (1). Hormones are known to have impor- tors have significant effects on bone remodeling, but neither tant effects on bone metabolism and have been studied exten- their synthesis nor their influence on cell metabolism are lim- sively, but recent work has revealed that growth factors also ited to the skeletal tissue. have significant effects on bone function. Growth factors are Transforming growth factor (TGF) f polypeptides that increase cell replication and have important effects on differentiated cell function. Initially growth factors TGFs are polypeptides isolated from normal and neoplastic were considered to act as systemic agents, but current evidence tissues and are known to alter normal cell growth (8). TGFs indicates that they act primarily as local regulators of cell induce nonneoplastic indicator cells to form anchorage-inde- growth. Individual growth factors are synthesized by multiple pendent colonies in soft agar suspension cultures, a process tissues and cell types and may act on cells of the same class that appears to be linked to neoplastic transformation. TGFs (autocrine factors) or on different cells (paracrine factors). have been categorized into TGFa and TGF#. TGFa has not Growth factors have been studied primarily in vitro and their been isolated from bone tissue and cannot be considered a exact role is still somewhat unclear, but their effects on cell local regulator of skeletal remodeling, although it is mitogenic replication and differentiation are pronounced and are likely for bone cells and stimulates bone resorption. TGFJ is a highly of physiological significance. conserved polypeptide with a molecular weight of 25,000 con- Recent work has revealed that bone cells synthesize a num- sisting of two subunits linked by disulfide bonds (8, 9). TGF3 ber of growth factors and that the bone matrix is a rich source is synthesized by many tissues, but bone and platelets are the of these polypeptides (2-4). Experimental data indicate that major sources for this factor (3). Three forms of TGF# have the two major processes of bone remodeling, bone formation been identified: TGFf 1, TGFf 2, and TGFf 1.2 (9). TGF3 1 and resorption, are closely regulated and that local factors play and TGFf 2 consist of two identical subunits and are present a critical role in their control. It is suspected that these factors in bone matrix and likely in bone cultures (2, 3). TGF3 1.2 is a mediate the effects of systemic hormones, which could modify heterodimer consisting of a TGFf 1 and a TGF# 2 chain, and the synthesis or effects of the local factors. Bone is a heteroge- its presence in skeletal tissue has not been reported. neous tissue comprised of a mixed cell population and is in Although the effects of TGF3 vary with the cell model and direct contact with cartilage and marrow cells; therefore, the the conditions of study, it is clear that TGF3 is an essential local regulators of bone remodeling may originate from a vari- regulator of cell replication and differentiation. TGFf 1 and 2 ety of cells. While true local regulators of bone metabolism are have - 70% homology in their amino acid sequence and have synthesized by skeletal cells, the bone matrix may trap sys- similar biological effects. TGFf stimulates bone DNA synthe- temic factors that could act as putative local regulators of bone sis and cell replication, and cells of the osteoblastic lineage are remodeling. These issues were taken into consideration when among the most sensitive to its mitogenic activity. TGFJ also classifying the local regulators of skeletal growth into (a) stimulates bone collagen synthesis, an effect that is in part growth factors synthesized by skeletal cells; (b) growth factors dependent on an increased number of osteoblasts; however, isolated from bone matrix; and (c) growth factors synthesized TGFf also regulates bone collagen synthesis by posttranscrip- by cells from adjoining tissues (Table I). tional mechanisms (10). The physiological role of TGFJ is uncertain. The multiple GROWTH FACTORS SYNTHESIZED BY SKELETAL CELLS biological activities of TGF3 and its synthesis by a variety of Studies performed by us and other investigators have shown cell types suggest that TGF# is an important growth regulator that cultured bones and bone cells synthesize a transforming of mammalian cells. In the skeletal system, TGF3, by itself or growth factor of the ,3 class, a bone-derived growth factor in conjunction with other growth regulators, has a major function in bone formation. The regulation of bone TGFf Address correspondence to Dr. Canalis, Saint Francis Hospital and synthesis by systemic hormones has not been reported, but its Medical Center, 114 Woodland St., Hartford, CT 06105. release from bone matrix is increased by hormones that induce Receivedfor publication 10 November 1987 and in revisedform 17 November 1987. 1. Abbreviations used in this paper: aFGF, acidic FGF; 12 m, beta2 microglobulin; BDGF, bone-derived growth factor; bFGF, basic FGF; J. Clin. Invest. ECGF, endothelial cell growth factor; FGF, fibroblast growth factor; K The American Society for Clinical Investigation, Inc. IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; 0021-9738/88/02/0277/05 $2.00 PTH, parathormone; Sm, somatomedin; TGF, transforming growth Volume 81, February 1988, 277-281 factor; TNFa, tumor necrosis factor a; TNF13, TNF13 or lymphotoxin. Growth Factors and Bone 277 Table L Growth Factors Involved in the Local Regulation modulates the binding of other growth factors or hormones to ofBone Remodeling their receptor. Factor Mr* Sm C Growth factors synthesized by skeletal cells Sm C or IGF I is a growth hormone-dependent polypeptide TGF( 25 that stimulates cartilage growth. There have been a number of BDGF or ,2 m 11.8 Sm's described, but only two have been characterized: IGF I SmCorIGFI 7.6 and IGF II. IGF I has a molecular weight of 7,600 and is PDGF 27-30 synthesized by multiple tissues, including bone and cartilage, Growth factors isolated from bone matrix but the synthesis of IGF II by skeletal cells has not been re- TGF,B 1 and 2 ported (6, 13, 14). Since multiple tissues synthesize Sm C, the BDGF function of the circulating hormone is uncertain, particularly Sm since the systemic administration of Sm C has only a marginal PDGF effect on cartilage growth. This observation supports the con- aFGF 17 cept that local Sm has a major role as a regulator of growth (6). bFGF 16 Detailed studies on the hormonal regulation of Sm C synthesis Growth factors synthesized by cells from by skeletal cells have not been reported, but growth hormone adjoining tissues stimulates Sm C synthesis in a variety of tissues and possibly in Cartilage bone (13, 14). Sm C Cultures of rat calvariae were recently found to synthesize bFGF a Sm C and to secrete one or more Sm-binding proteins (6). In Blood cells bone cultures, Sm C stimulates the replication of preosteo- Monokines blastic cells; consequently, it increases the number of osteo- IL-1 17.5 blasts capable of synthesizing bone matrix (15). Sm C also has TNFa 1 7 a direct stimulatory effect on osteoblastic differentiated func- Macrophage-derived growth factors 10, 40 tion that is independent from that on cell replication; thus, Sm PDGF C stimulates bone matrix synthesis by two different mecha- Lymphokines nisms. Sm C has no effect on bone resorption. tissue Lymphotoxin or TNF# 18.6 Since (2 m and Sm C have similar effects on skeletal INFy 15-25 and since (2 m is known to modulate the effects of other hormones on cell function, one may speculate that (32 m plays a role in the regulation of the action of the locally produced Sm * Mr, Molecular mass X l0-3. C on skeletal metabolism. Other molecules suspected of mod- ulating the availability or effects of Sm C on bone cell function bone resorption such as parathormone (PTH) (1 1). In addi- are Sm-binding proteins ( 16). These proteins are considered to tion, PTH enhances the binding of TGF# to its osteoblast have a number of functions including the transport of Sm, receptor, and these two effects may be critical in the coupling prolongation of its half-life, and modulation of Sm activity, of bone formation to bone resorption (Centrella, M., unpub- but their exact function in the skeletal tissue has not been lished observations). established. BDGF Platelet-derived growth factor (PDGF) BDGF has been isolated from bone matrix and calvarial cul- PDGF is a two-chain polypeptide with an Mr of 27,000- tures, and recent evidence from our laboratory identified it as 30,000 (17). The original source of PDGF was platelets, but beta2 microglobulin ((2 m) (5), a polypeptide with a molecular PDGF or PDGF-like peptides have been isolated from a vari- weight of 11,800. BDGF, or (2 m, stimulates bone collagen ety of normal and neoplastic tissues, including bone matrix and DNA synthesis in calvarial cultures; the effect is smaller and osteosarcoma cells (4, 7). PDGF stimulates bone DNA than that seen with other growth factors and is observed at and protein synthesis, and may be a systemic or a local regula- 0.1-50 ,ug/ml.