Editorial

Connective Tissue Growth Factor: A Key Factor Among
Mediators of Tissue Fibrosis

Nader Sheibani1,2,3,4, PhD

1Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison,
WI, USA

2Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
3McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

4Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA

ORCID:
Nader Sheibani: https://orcid.org/0000-0003-2723-9217

J Ophthalmic Vis Res 2022; 17 (4): 449–452

Fibrosis is the increased accumulation of
fibrous connective tissue in and around tissues
with inflammation or damage, which initiates
irreversible scar formation.[1] It is a main reason
for the development of adverse events in many
chronic inflammatory diseases. Despite many
efforts in the development of therapeutics for
fibrosis, success has been very limited. However,
recent advancements in single cell omics’ tools
are helping to delineate the molecular and
cellular mechanisms that contribute to fibrosis and
provide the opportunity for more targeted new
approaches for treatment of fibrosis.[2] Fibrosis
contributes to disorders in many tissues and organs
including liver and heart dysfunction, rheumatoid
arthritis, diabetic nephropathy and retinopathy,
age-related macular degeneration, corneal
wound healing, and glaucoma.[1, 3] However,

Correspondence to:

Nader Sheibani, PhD. Department of Ophthalmology
and Visual Sciences, University of Wisconsin, School of
Medicine and Public Health, Madison, WI 53705, USA.
Email: nsheibanikar@wisc.edu
Received: 10-08-2022 Accepted: 27-08-2022

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v17i4.12294

the underlying cellular and molecular
mechanisms may vary in different organs, and the
commonality among these diverse fibrotic diseases
is not fully delineated. Connective tissue growth
factor (CTGF) has been recognized as an important
mediator of fibrosis and scar formation.[4–11] A
recent study utilizing computational strategies
identified CTGF as the common key molecule
regulating fibrogenesis among eight different
fibrotic diseases including ocular fibrosis.[12]
Thus, many efforts have focused on interfering
with the expression and activity of CTGF,
such as function blocking antibodies,[13–16]
siRNA,[17, 18] shRNA,[19] microRNA,[20, 21] Yap/Taz
inhibitor,[22–24] and most recently CRISPER-
Cas9 system[25] to mitigate fibrosis in different
cells, tissues, and organs including the eye.
Fibrosis is a complex and active process, which
is impacted by various cell types, differentiation
and signaling pathways, genes, and crosstalk.[1, 26]

This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

How to cite this article: Sheibani N. Connective Tissue Growth
Factor: A Key Factor Among Mediators of Tissue Fibrosis. J
Ophthalmic Vis Res 2022;17:449–452.

© 2022 Sheibani. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED BY KNOWLEDGE E 449

http://crossmark.crossref.org/dialog/?doi=10.18502/jovr.v17i4.12294&domain=pdf&date_stamp=2019-07-17
https://knepublishing.com/index.php/JOVR


Editorial; Sheibani

The deposition of excessive extracellular matrix
proteins by myofibroblasts is common to many
fibrotic conditions.[27–29] Perivascular supporting
cells, which are also tissue resident mesenchymal
stem cells, are recently recognized as being
the cells primarily involved in fibrotic responses
in many organs and tissues.[30] We have noted
that retinal and choroidal perivascular supporting
cells express higher levels of CTGF compared
to retinal or choroidal endothelial cells but lower
than microglial and retinal pigment epithelial
cells (our unpublished observations). The high
levels of CTGF in microglial cells decreases
while that of pericytes increases in response
to high glucose conditions,[31] and may drive
migration and/or loss of perivascular cells from
retinal blood vessels during diabetes.[32] Immune
cells, such as macrophages, mediate inflammatory
responses that are integrated with other pro-
fibrotic processes.[29, 31, 33–35] However, the details
of these interactions remain poorly understood, but
single-cell genomic, proteomic, and transcriptomic
techniques are further unraveling the specific cell
subtypes and their interactions in pathophysiology
of fibrosis in various tissues.

In terms of signaling pathways, TGF-β has
been extensively recognized as key mediator
of pro-fibrotic activity.[3] Since the protein is
made as an inactive precursor and deposited in
the extracellular matrix (ECM), its mechanisms
of activation by αvβ6 integrin, autotaxin, and
galectin-3 have been targeted for potential
therapeutics.[1, 3] Unfortunately, targeting these
mechanisms of TGF-β activation have been
ineffective in treating and/or preventing fibrosis,
especially in idiopathic pulmonary fibrosis.[26]
These failures have been attributed, at least in
part, to normal physiological functions of TGF-β,
and its systemic inactivation could have many
adverse effects. Thus, not only the identification of
pathways involved are important but determining
their hierarchy is essential to their successful
targeting for therapeutic intentions. CTGF is a
downstream target of TGF-β in tissue remodeling
and ECM synthesis. It is also proinflammatory and
is recognized as a common key driver of fibrosis
in various fibrotic disorders.[12] Thus, focusing on
the role of inflammatory cells and their mediators
in modulation of innate immune cell responses in
driving fibrosis could be beneficial.[26] Revealing
the identity, organization, and mechanical
properties of the ECM environment in fibrosis

could also provide additional unique clues to the
mechanisms that drives inappropriate activation of
target cells.

Trabeculectomy is a surgical treatment to
lower intraocular pressure in glaucoma patients.
However, excess scaring leads to failure of the
filtering bleb and adversely affect the treatment
outcome.[36, 37] It is well-established that CTGF
expression is significantly upregulated during
this fibrotic response and targeting CTGF using
various modalities, as stated above, are shown to
prevent fibrotic signaling including proliferation,
ECM deposition, and proinflammatory activity in
fibroblasts and retinal pigment epithelial cells, and
in in vivo preclinical models. In a manuscript in
this issue of JOVR, Hassanpour and colleagues[38]
demonstrate subconjunctival delivery of anti-
CTGF is efficacious in prolonging the bleb life
in a rabbit model of trabeculectomy. They did a
careful analysis of the microstructural features of
the bleb areas and provide histological proof on
the inhibition or reduction of fibrosis in anti-CTGF
treated trabeculectomy blebs. The changes in
response to anti-CTGF were comparable with
those noted in mitomycin C (MMC) treatment. They
also showed MMC treatment was concomitant with
decreased production of CTGF, likely as a result of
the inhibition of cell proliferation by MMC. Growth
arrested cells, a limitation with use of MMC, are
however metabolically active and could release
other factors, which could exacerbate fibrosis.

The recognition of CTGF as the common factor
in driving fibrosis in various organs with fibrosis
supports an import role for antagonism of CTGF
for treatment of these diseases. The same group
has previously shown that anti-CTGF is efficacious
in mitigating fibrosis in preclinical models of
neovascular age-related macular degeneration
and proliferative vitreoretinopathy with minimal
adverse effect on vision.[14, 16, 39] Thus, a better
understanding of the mechanisms of CTGF
action and its cell autonomous activities may
aid in development of new and complementary
agents with effective antifibrotic activity. Recent
studies have also identified the hippo signaling
pathway and its downstream effectors YAP/TAZ
as important modulator of CTGF production and
activity.[22] The YAP/TAZ inhibitor, verteporfin,
suppresses CTGF production and mitigates
fibrosis in the eye and heart.[23, 40, 41] We are
beginning to know more about the expression and
function of CTGF using transgenic mice including

450 JOURNAL OF OPHTHALMIC AND VISION RESEARCH Volume 17, Issue 4, October-December 2022



Editorial; Sheibani

CTGF reporter, and global and conditional CTGF
null mice.[2, 42–44] We are learning about the
role of CTGF in normal developmental and
repair processes.[43] A recent study targeting the
deletion of CTGF in endothelial cells demonstrated
an import role for CTGF-YAP axis for retinal
angiogenesis and barrier formation.[2] In addition,
deletion of CTGF in corneal epithelial cells
interfere with proper corneal wound healing.[43]
Thus, a better understanding of how CTGF, and
perhaps other mediators, aberrant expression
and downstream signaling events are regulated
during early and late stages of fibrotic diseases
will help to identify the common and unique
regulatory mechanisms involved. We recently
identified Bim expression, a proapoptotic member
of Bcl-2 family, as essential for clearance of
macrophages and mitigation of fibrosis in a
preclinical model of choroidal neovascularization
and scar formation.[45] Although there are some
common pathways engaged by fibrosis in different
organs, there are also unique pathways which we
know little about. Identification of these unique
pathways and elucidation of their interactions
will allow development of organ specific anti-
fibrotic agents, which are tissue specific and more
effective for treatment of fibrosis.

Financial Support and Sponsorship

None.

Conflicts of Interest

There are no conflicts of interest.

REFERENCES

1. Mallone F, Costi R, Marenco M, Plateroti R, Minni A,
Attanasio G, et al. Understanding drivers of ocular fibrosis:
Current and future therapeutic perspectives. Int J Mol Sci
2021;22:11748. https://doi.org/10.3390/ijms222111748

2. Moon S, Lee S, Caesar JA, Pruchenko S, Leask A, Knowles
JA, et al. A CTGF-YAP regulatory pathway is essential for
angiogenesis and barriergenesis in the retina. Iscience
2020;23:101184.

3. Hachana S, Larrivée B. TGF-β; superfamily signaling
in the eye: Implications for ocular pathologies. Cells
2022;11:2336.

4. Razzaque MS, Foster CS, Ahmed AR. Role of connective
tissue growth factor in the pathogenesis of conjunctival
scarring in ocular cicatricial pemphigoid. Invest
Ophthalmol Vis Sci 2003;44:1998–2003.

5. He S, Jin ML, Worpel V, Hinton DR. A role for connective
tissue growth factor in the pathogenesis of choroidal
neovascularization. Arch Ophthalmol 2003;121:1283–
1288.

6. He S, Chen Y, Khankan R, Barron E, Burton R, Zhu D,
et al. Connective tissue growth factor as a mediator
of intraocular fibrosis. Invest Ophthalmol Vis Sci
2008;49:4078–4088.

7. Junglas B, Kuespert S, Seleem AA, Struller T, Ullmann
S, Bösl M, et al. Connective tissue growth factor causes
glaucoma by modifying the actin cytoskeleton of the
trabecular meshwork. Am J Pathol 2012;180:2386–2403.

8. Kuiper EJ, de Smet MD, van Meurs JC, Tan HS, Tanck MW,
Oliver N, et al. Association of connective tissue growth
factor with fibrosis in vitreoretinal disorders in the human
eye. Arch Ophthalmol 2006;124:1457–1462.

9. Esson DW, Neelakantan A, Iyer SA, Blalock TD,
Balasubramanian L, Grotendorst GR, et al. Expression of
connective tissue growth factor after glaucoma filtration
surgery in a rabbit model. Invest Ophthalmol Vis Sci
2004;45:485–491.

10. Junglas B, Yu AH, Welge-Lüssen U, Tamm ER, Fuchshofer
R. Connective tissue growth factor induces extracellular
matrix deposition in human trabecular meshwork cells.
Exp Eye Res 2009;88:1065–1075.

11. Daniels JT, Schultz GS, Blalock TD, Garrett Q, Grotendorst
GR, Dean NM, et al. Mediation of transforming growth
factor-beta(1)-stimulated matrix contraction by fibroblasts:
a role for connective tissue growth factor in contractile
scarring. Am J Pathol 2003;163:2043–2052.

12. Gu C, Shi X, Dang X, Chen J, Chen C, Chen Y, et al.
Identification of common genes and pathways in eight
fibrosis diseases. Front Genet 2020;11:627396.

13. Wang JM, Hui N, Fan YZ, Xiong L, Sun NX. Filtering bleb
area and intraocular pressure following subconjunctival
injection of CTGF antibody after glaucoma filtration
surgery in rabbits. Int J Ophthalmol 2011;4:480–483.

14. Daftarian N, Rohani S, Kanavi MR, Suri F, Mirrahimi
M, Hafezi-Moghadam A, et al. Effects of intravitreal
connective tissue growth factor neutralizing antibody on
choroidal neovascular membrane-associated subretinal
fibrosis. Exp Eye Res 2019;184:286–295.

15. Bagheri A, Soheili ZS, Ahmadieh H, Samiei S, Sheibani
N, Astaneh SD, et al. Simultaneous application of
bevacizumab and anti-CTGF antibody effectively
suppresses proangiogenic and profibrotic factors in
human RPE cells. Mol Vis 2015;21:378–390.

16. Daftarian N, Baigy O, Suri F, Kanavi MR, Balagholi
S, Afsar Aski S, et al. Intravitreal connective tissue
growth factor neutralizing antibody or bevacizumab
alone or in combination for prevention of proliferative
vitreoretinopathy in an experimental model. Exp Eye Res
2021;208:108622.

17. Lim DH, Kim TE, Kee C. Evaluation of adenovirus-
mediated down-regulation of connective tissue growth
factor on postoperative wound healing after experimental
glaucoma surgery. Curr Eye Res 2016;41:951–956.

18. Jing J, Li P, Li T, Sun Y, Guan H. RNA interference targeting
connective tissue growth factor inhibits the transforming
growth factor- β 2 induced proliferation in human tenon
capsule fibroblasts. J Ophthalmol 2013;2013:354798.

JOURNAL OF OPHTHALMIC AND VISION RESEARCH Volume 17, Issue 4, October-December 2022 451



Editorial; Sheibani

19. Lei D, Dong C, Wu WK, Dong A, Li T, Chan MT, et al.
Lentiviral delivery of small hairpin rna targeting connective
tissue growth factor blocks profibrotic signaling in
tenon’s capsule fibroblasts. Invest Ophthalmol Vis Sci
2016;57:5171–5180.

20. Wang WH, Deng AJ, He SG. A key role of microrna-26a
in the scar formation after glaucoma filtration surgery. Artif
Cells Nanomed Biotechnol 2018;46:831–837.

21. Bao H, Jiang K, Meng K, Liu W, Liu P, Du Y, et al. TGF-
β2 induces proliferation and inhibits apoptosis of human
Tenon capsule fibroblast by mir-26 and its targeting of
CTGF. Biomed Pharmacother 2018;104:558–565.

22. Futakuchi A, Inoue T, Wei FY, Inoue-Mochita M, Fujimoto
T, Tomizawa K, et al. YAP/TAZ are essential for TGF-β2-
mediated conjunctival fibrosis. Invest Ophthalmol Vis Sci
2018;59:3069–3078.

23. Chen WS, Cao Z, Krishnan C, Panjwani N. Verteporfin
without light stimulation inhibits YAP activation in
trabecular meshwork cells: Implications for glaucoma
treatment. Biochem Biophys Res Commun 2015;466:221–
225.

24. Liu Z, Li S, Qian X, Li L, Zhang H, Liu Z. Rhoa/ROCK-
YAP/TAZ axis regulates the fibrotic activity in
dexamethasone-treated human trabecular meshwork
cells. Front Mol Bioscis 2021;8:728932.

25. Lee EJ, Han JC, Park DY, Cho J, Kee C. Effect of connective
tissue growth factor gene editing using adeno-associated
virus-mediated CRISPR-Cas9 on rabbit glaucoma filtering
surgery outcomes. Gene Ther 2021;28:277–286.

26. Fang Y, Tian J, Fan Y, Cao P. Latest progress on the
molecular mechanisms of idiopathic pulmonary fibrosis.
Mol Biol Rep 2020;47:9811–9820.

27. Wilson SE. Fibrosis is a basement membrane-related
disease in the cornea: injury and defective regeneration
of basement membranes may underlie fibrosis in other
organs. Cells 2022;11.

28. Wallace DM, Murphy-Ullrich JE, Downs JC, O’Brien CJ.
The role of matricellular proteins in glaucoma. Matrix Biol
2014;37:174–182.

29. Nikhalashree S, Karthikkeyan G, George R, Shantha B,
Vijaya L, Ratra V, et al. Lowered decorin with aberrant
extracellular matrix remodeling in aqueous humor and
tenon’s tissue from primary glaucoma patients. Invest
Ophthalmol Vis Sci 2019;60:4661–4669.

30. Kramann R, Schneider RK, dirocco DP, Machado F, Fleig
S, Bondzie PA, et al. Perivascular Gli1+ progenitors are key
contributors to injury-induced organ fibrosis. Cell Stem Cell
2015;16:51–66.

31. Kuiper EJ, Witmer AN, Klaassen I, Oliver N,
Goldschmeding R, Schlingemann RO. Differential
expression of connective tissue growth factor in
microglia and pericytes in the human diabetic retina.
Br J Ophthalmol 2004;88:1082–1087.

32. Liu H, Yang R, Tinner B, Choudhry A, Schutze N, Chaqour
B. Cysteine-rich protein 61 and connective tissue growth

factor induce deadhesion and anoikis of retinal pericytes.
Endocrinology 2008;149:1666–1677.

33. Seher A, Nickel J, Mueller TD, Kneitz S, Gebhardt S, ter
Vehn TM, et al. Gene expression profiling of connective
tissue growth factor (CTGF) stimulated primary human
tenon fibroblasts reveals an inflammatory and wound
healing response in vitro. Mol Vis 2011;17:53–62.

34. Suzuma K, Naruse K, Suzuma I, Takahara N, Ueki
K, Aiello LP, et al. Vascular endothelial growth factor
induces expression of connective tissue growth factor
via KDR, Flt1, and phosphatidylinositol 3-kinase-akt-
dependent pathways in retinal vascular cells. J Biol Chem
2000;275:40725–40731.

35. Tanaka S, Zheng S, Kharel Y, Fritzemeier RG, Huang
T, Foster D, et al. Sphingosine 1-phosphate signaling in
perivascular cells enhances inflammation and fibrosis in
the kidney. Sci Transl Med 2022;14:eabj2681.

36. Rao A, Cruz RD. Trabeculectomy: Does it have a future?
Cureus 2022;14:e27834.

37. Koike KJ, Chang PT. Trabeculectomy: A brief history and
review of current trends. Int Ophthalmol Clin 2018;58:117–
133.

38. Hassanpour K, Rezaei Kanavi M, Daftarian N, Samaeili
A, Suri S, Parkravan M, et al. The inhibitory effect of
connective tissue growth factor antibody on postoperative
fibrosis in a rabbit model of trabeculectomy. J Ophthalmic
Vis Res 2022;17;4:486–496.

39. Motevasseli T, Daftarian N, Kanavi MR, Ahmadieh H,
Bagheri A, Hosseini SB, et al. Ocular safety of intravitreal
connective tissue growth factor neutralizing antibody. Curr
Eye Res 2017;42:1194–1201.

40. Garoffolo G, Casaburo M, Amadeo F, Salvi M, Bernava
G, Piacentini L, et al. Reduction of Cardiac fibrosis by
interference with YAP-dependent transactivation. Circ Res
2022;131:239–257.

41. Ho LTY, Skiba N, Ullmer C, Rao PV. Lysophosphatidic
acid induces ECM Production via activation of the
mechanosensitive YAP/TAZ transcriptional pathway in
trabecular meshwork cells. Invest Ophthalmol Vis Sci
2018;59:1969–1984.

42. Dillinger AE, Kuespert S, Froemel F, Tamm ER, Fuchshofer
R. CCN2/CTGF promotor activity in the developing and
adult mouse eye. Cell Tissue Res 2021;384:625–641.

43. Gibson DJ, Pi L, Sriram S, Mao C, Petersen BE, Scott EW,
et al. Conditional knockout of CTGF affects corneal wound
healing. Invest Ophthalmol Vis Sci 2014;55:2062–2070.

44. Kuiper EJ, Roestenberg P, Ehlken C, Lambert V, van
Treslong-de Groot HB, Lyons KM, et al. Angiogenesis is not
impaired in connective tissue growth factor (CTGF) knock-
out mice. J Histochem Cytochem 2007;55:1139–1147.

45. Wang S, Zaitoun IS, Darjatmoko SR, Sheibani
N, Sorenson CM. Bim expression promotes the
clearance of mononuclear phagocytes during choroidal
neovascularization, mitigating scar formation in mice. Life
2022;12:208.

452 JOURNAL OF OPHTHALMIC AND VISION RESEARCH Volume 17, Issue 4, October-December 2022