Opposing Roles of BMP and TGF-β Signaling
Pathways in Pancreatitis: Mechanisms and
Yanna Cao*, Madeline Drake, Joy Davis, Baibing Yang and Tien C Ko
Department of Surgery, The University of Texas Health Science Center, USA
Submission: August 21, 2019; Published:September 04, 2019
*Corresponding author:Yanna Cao, Department of Surgery, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
How to cite this article: Yanna Cao, Madeline Drake, Joy Davis, Baibing Yang, Tien C Ko. Opposing Roles of BMP and TGF-β Signaling Pathways in
Pancreatitis: Mechanisms and Therapeutic Implication. Adv Res Gastroentero Hepatol. 2019;13(5): 555871. DOI: 10.19080/ARGH.2019.13.555871.
Bone morphogenetic proteins (BMPs) comprise a major subgroup of the transforming growth factor (TGF)-β superfamily. They play pivotal roles in embryonic development and tissue homeostasis in adults. Deregulation of BMP and TGF-β signaling contributes to developmental anomalies and multiple diseases. In this mini-review, we focus on BMP signaling in inflammatory disorders of the pancreas, acute and chronic pancreatitis, in contrast to TGF-β signaling. We then discuss molecular mechanisms that interact with and connect between the BMP and TGF-β signaling pathways. Lastly, we review potential implications of these molecular mechanisms for therapeutic development. In summary, BMP signaling pathway plays different roles during pancreatitis disease development, and the antagonism between BMP and TGF-β signaling can be manipulated for therapeutic development against pancreatitis.
Bone morphogenetic proteins (BMPs) constitute a major subgroup of the transforming growth factor (TGF)-β superfamily, comprising 18 (several also named as growth differentiation factors) out of the total 33 members . The TGF-β/BMP superfamily plays pivotal roles in embryonic development and tissue homeostasis in adults. Deregulation of the TGF-β/BMP signaling contributes to developmental anomalies and multiple diseases [1,2]. The TGF-β/BMP superfamily signals through a complex of membrane-associated serine/threonine kinase receptors. In the canonical signaling pathway, BMP ligand binds to BMP receptors type I (BMPR1) and type II (BMPR2) on the cell surface and subsequently activates intracellular mediators Smad1/5/8 via phosphorylation . In parallel, TGF-β binds to TGF-β receptors TβRI and TβRII and activates Smad2/3. The phosphorylated Smad1/5/8 or pSmad2/3 form complexes with Smad4, which translocates to the nucleus to regulate transcription of target genes [4,5]. Activation of specific Smads may lead to distinct or opposing biological outcomes,most notably in disease states [3,6,7]. Both BMP and TGF-β also activate other non-canonical signaling pathways [8,9]. BMP signaling can be regulated at the extracellular, membrane, and intracellular level. The most investigated molecules that negatively regulate BMP signaling extracellularly are the BMP antagonists, which sequester BMPs and prevent their interaction with the cell surface receptors. Over 12 members of endogenous BMP antagonists have been identified to date [3,10].
Lines of evidence demonstrate that BMP signaling has pro-inflammatory properties in bronchial epithelial cells during airway inflammation , in activated endothelial cells , and in atherosclerotic arteries . Paradoxically, BMP signaling has anti-fibrogenic functions in several organs, including kidneys, lungs, and liver [14-16]. However, the role of BMP signaling in the pancreas, specifically within pancreatic inflammatory disease processes, is unclear
In recent years, our group has focused on the role of BMP signaling in acute (AP) and chronic pancreatitis (CP), the highly debilitating and painful inflammatory diseases of the pancreas.
While a majority of AP cases self-resolve, approximately 16%
progress to CP after repeated episodes of AP (RAP), mainly in
patients with risk factors like alcohol and tobacco use [17,18]. CP
is the #1 cause of Type 3c Diabetes , and a major risk factor
for pancreatic cancer, one of the most lethal cancer types .
Unfortunately, the standard care for pancreatitis lacks specific
pharmacological therapies, and remains primarily supportive.
Thus, there is a pressing need to identify key mechanisms
contributing to the disease development and progression, in
order to develop innovative therapeutic strategies for blocking
and reversing the pancreatic destruction associated with
CP; ultimately, reducing the risk for developing diabetes and
pancreatic cancer in these patients.
To understand the role of BMPs in AP, we utilized experimental
animal and cell models, and revealed that BMP/Smad1/5
signaling is activated; inhibition of BMP signaling attenuates
the disease severity, indicating a pro-inflammatory role of BMP
signaling in AP . The role of TGF-β signaling is controversial,
with both pro-inflammatory and anti-inflammatory roles
reported . However, due to a lack of availability of most
human AP samples, our study regarding BMP signaling is only
proof-of-concept. Much work is needed to establish clinical
relevance by identifying secreted factors of the TGF-β/BMP
superfamily from patient blood and pancreatic juice, in addition
to further study of the mechanisms in experiment models.
Several studies from our group have demonstrated opposing
roles of BMP and TGF-β in CP. For instance, in pancreatic stellate
cells, the key executive cells in pancreatic fibrosis, BMP2 alone
does not induce extracellular matrix (ECM) expression but
inhibits TGF-β induced-ECM production . Knockout of
BMPR2 in mice exacerbates CP, leading to enhanced inflammation
and fibrosis, two hallmarks of CP . These findings reveal a
protective and anti-fibrogenic role of BMP signaling in CP, in
contrast to the pro-fibrogenic TGF-β signaling [25,26].
To search for molecular links between BMP and TGF-β,
we focus on Gremlin1 (Grem1), a BMP antagonist, which has
reported pro-fibrogenic function in several organs [15,27,28].
We demonstrated increased levels of Grem1 in human and
mouse CP, associated with elevated TGF-β. TGF-β can induce
Grem1, and Grem1 can block BMP2 induced Smad1/5 signaling
in pancreatic stellate cells. Knockout of Grem1 in mice attenuates
pancreatic fibrosis . These findings propose a feed-forward
loop between TGF-β, Grem1, and BMP, in which Grem1 may act
as a nodal point between the pro-fibrogenic TGF-β and the antifibrogenic
BMP signaling pathways. Thus, the level of Grem1
expression may define the disease progression from AP, RAP, to
CP (Figure 1).
Overall, temporal changes of the TGF-β/BMP signaling
molecules and Grem1 during disease progression from AP to
CP [23,24,29,30], provide rationale for further translational
study. Since TGF-β has a broad spectrum of biological functions,
systemic TGF-β blockade may yield unexpected or detrimental
effects. To circumvent these effects, modulation of TGF-β downstream
mediators and of the opposing BMP signaling that
desensitize cellular responses to TGF-β or antagonize TGF-β
signal transduction should be explored. Thus, the therapeutic
goal is to restore or up-regulate the anti-fibrogenic BMP
signaling pathway and to counteract the pro-fibrogenic TGF-β
signaling pathway. This can be executed by time-dependently
administering the Grem1 neutralization antibody  or
specific microRNAs [32,33] that can inhibit Grem1 as well as
release suppression on BMP signaling, or in combination with
the specific small molecules or peptides that can activate BMP
Studies on the different roles and the reciprocal regulation
of BMP and TGF-β not only advance our knowledge on how the
same superfamily members regulate each other’s functions in diseased states, but also provide insights on how the
antagonistic roles of BMP and TGF-β signaling can be modulated
as therapeutic approaches.