Table 1.

Summary of evidence for TGF-β ligands in fibrosis.

LIGAND	Signaling pathway	ANTI/PRO-fibrotic	Liver fibrosis	Kidney fibrosis	Cardiac fibrosis	Muscle fibrosis	Lung fibrosis	Examples of therapeutic approaches
TGF-β1/ TGF-β2	TGF-β1 uses TGF-βRI (ALK5), TGF-βRII, and induces SMAD 2/3 signal. TGF-β2 also uses TGF-βRIII (betaglycan)	PRO	TGF-β1 induces α-SMA and type 1 collagen expression, and promotes migration/invasion of hepatic stellate cells (HSCs), the major producers of collagen in the liver (Presser et al., 2013). TGF-β2 accumulates in the bile ducts in human fibrotic liver disease, encouraging collagen deposition (Milani et al., 1991).	TGF-β1 drives differentiation of renal epithelial cells into α-SMA positive myofibroblasts, which also secrete collagen (Fan et al., 1999). In human glomerular disease, TGF-β1 protein expression is positively correlated with interstitial fibrosis severity and ECM production (Goumenos et al., 2001).	TGF-β1 and ECM production is upregulated following cardiac infarction in rats. Exogenous TGF-β1 can drive myocardial fibrosis in vivo. Cardiac fibroblasts differentiate into myofibroblasts in the presence of TGF-β1 (summarized in Lijnen et al., 2000).	High levels of TGF-β1 promote increased ECM deposition and attract inflammatory cells during muscle repair (summarized in Delaney et al., 2017). TGF-β1 expression is upregulated in dystrophic patients (Bernasconi et al., 1999).	TGF-β1 induces severe fibrosis in rat lungs, and is upregulated in patients suffering idiopathic pulmonary fibrosis (IPF) (Sime et al., 1997; Molina-Molina et al., 2006).	Small molecule inhibitor PirfenidoneTM (Azuma, 2012) has been approved for the treatment of IPF. TGF-β1 targeting mAbs have also been tested in human IPF patients (Voelker et al., 2017), and TGF-β2 mAbs have anti-scaring activity in human glaucoma patients (Mead et al., 2003).
TGF-β3	TGF-βRI (ALK5), TGF-βRII, induces SMAD 2/3 signal	ANTI	TGF-β3 can alleviate the degree of hepatic fibrosis and tissue injury via the suppression of type 1 collagen synthesis (Zhang et al., 2010).			TGF-β3 is upregulated in muscle fibrosis, but competes with the pro-fibrotic TGF-β1 activity (Zhao et al., 2010).		Recombinant TGF-β3 (JuvistaTM) demonstrated to improve wound healing during clinical trials (Ferguson et al., 2009).
Activin A	ActRIIA/ActRIIB, ALK4/7, induces SMAD 2/3 signal	PRO	Activin A is upregulated in rat models of liver fibrosis, and drives collagen production from hepatocytes (Sugiyama et al., 1998). Activin A is produced by activated HSCs in vitro and in vivo, and its activity appears to be unopposed by follistatin (Patella et al., 2006).	Activin A promotes cell proliferation, induces differentiation into myofibroblasts, and promotes expression of collagen in primary cultured renal interstitial fibroblasts in rats (Yamashita et al., 2004). Activin A expression is upregulated in multiple mouse models of chronic kidney disease (Agapova et al., 2016).	Heart failure patients have elevated activin A serum levels, which correlate with disease severity. Cardiomyocytes are the primary source of activin A production in the heart as it fails (Yndestad et al., 2004).	Activin A hyper-expression promotes muscle fibrosis, as evidenced by an increase in differentiated myofibroblasts and accompanied increase in ECM deposition (Chen et al., 2014).	Activin A expression is increased in cystic fibrosis (CF) patients, and activin inhibition reduces disease progression in a mouse model of CF (Hardy et al., 2015). Serum activin A and B concentrations are elevated in critically ill patients suffering acute respiratory failure (de Kretser et al., 2013).	Follistatin can improve muscle function and reduce fibrosis in two models of muscle disease (Mendell et al., 2015, 2017). Other ligands traps such as sActRII and propeptides work effectively in mouse models of activin-induced fibrosis (Chen et al., 2015; Agapova et al., 2016).
Myostatin	ActRIIA/ActRIIB, ALK4/5, induces SMAD 2/3 signal	PRO			Exogenous expression of myostatin from cardiomyocytes promotes interstitial fibrosis (Biesemann et al., 2015), and myostatin expression is increased following heart injury (Sharma et al., 1999). Aging hearts in myostatin null mice exhibit reduced fibrosis (Morissette et al., 2009).	Myostatin is a negative regulator of muscle mass and overexpression results in a pro-fibrotic response, with increased myofibroblasts and ECM production (Li et al., 2008).		Follistatin and soluble ActRII blocked myostatin signaling during clinical trials, leading to a reduction in fibrosis (Attie et al., 2013; Mendell et al., 2015; Campbell et al., 2016).
BMP7	BMPRII, BMPRI (ALK3/6), induces SMAD 1/5/8 signal	ANTI	BMP7 demonstrated to inhibit liver fibrosis and suppress activation of HSCs, via downregulation of TGF-β1 and α-SMA (Wang et al., 2014).	BMP7 expression decreases in renal fibrosis, and exogenous BMP-7 is protective in multiple animal models of nephropathies (summarized in Li et al., 2015).	BMP7 activates infiltrating monocytes into anti-inflammatory M2 macrophages, which inhibits apoptosis and fibrosis in prediabetic cardiomyopathy (Urbina and Singla, 2014).		BMP7 significantly reduced the progression of silica-induced fibrosis in rats, via upregulation of the SMAD1/5/8 axis and downregulation of SMAD2/3 signaling (Yang et al., 2013).	A BMP7 mimetic, AA123, demonstrated anti-fibrotic effects in a mouse model of kidney disease (Sugimoto et al., 2012).
BMP9	BMPRII, BMPRI (ALK1/5), induces SMAD 1/5/8 signal	PRO	BMP-9 promotes liver fibrosis via HSC differentiation, and promotes collagen 1 and fibronectin production (Bi and Ge, 2014; Breitkopf-Heinlein et al., 2017). BMP9 appears to mediate these actions through ALK1/5 (Munoz-Felix et al., 2016).					BMP-9 derivatives have been examined as bone regenerative agents (Bergeron et al., 2009, Bergeron et al., 2012). No specific BMP-9 intervention has been trialed to date for fibrosis therapy.