Osteoarthritis (OA) is a degenerative form of arthritis leading to joint disability. It
has been estimated that more than 15% of world’s population have joint diseases, and
more than 27 million Americans have OA. Furthermore, European Union has more than
39 million people with OA, and probably by 2020, these numbers will be doubled. Multiple
factors induce OA leading to stimulate articular cartilage chondrocytes to produce the
proteolytic enzymes these enzymes included matrix metalloproteinases (MMPs) and a
disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) which work
together to degrade joint articular cartilage leading to osteophyte formation and stiffening
of joints. So far, there are no medications that can treat OA, and all medicines such as analgesics, corticosteroids, and non-steroid anti-inflammatory drugs (NSAIDs) are used
to reduce the pain and inflammation.
GPNMB also called Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB)
is a type I transmembrane glycoprotein expressed in multiple cell types and involved in
multiple cell functions such as proliferation, differentiation, and apoptosis. Studies
discovered the role of GPNMB in tumors, neurons, muscles, and bones while the role of
GPNMB in cartilage is unknown. Our study aims to discover the role of GPNMB in
cartilage homeostasis in post-traumatic OA.
microRNA (miRNA) is a small non-coding RNA consisting of ~22 nucleotides which
regulate gene expression through targeting the 3’UTR region of the target mRNA. miRNA
accounts for 1-5% of the human genome and regulate at least 30% of protein-coding
genes and are involved in cells functions regulation. In our study, we focused on the
impact miRNA-150 on GPNMB in vivo and in vitro.
The current study is composed of three hypothesizes. First, GPNMB has an anti-inflammatory
role in osteoarthritis by reducing the catabolic genes such as MMP-3, MMP-
9, MMP-13, ADAMTS4, and interleukin-6 (IL-6). Second, GPNMB is negatively regulated
by miRNA-150 in chondrocytes. Third, GPNMB binds to the CD44 receptor in articular
chondrocytes leading to the inhibition of pERK and p-NFkB-65.
Five mouse models were used in this study to define the function, mechanism, and
regulation of GPNMB in cartilage which involved C57BL/6, DBA/2J, DBA/2J Gpnmb+,
CD44 knockout and miRNA-150 knockout mice.
Our data showed that GPNMB is expressed in normal articular chondrocytes, and
expression level was higher in damaged cartilage. IL-1ß- induced inflammatory factors
involved interleukin-6 (IL-6) and cartilage degradation enzymes such as MMP-3, MMP-9,
MMP-13 and ADAMTS4 were downregulated following extracellular domain GPNMB
treatment. Furthermore, immunoprecipitation data showed that GPNMB binds to the
CD44 receptor in chondrocytes. We also found that GPNMB inhibits pERK and pNFkB-
65 proteins through the CD44 receptor. We also showed that miRNA-150 regulate
GPNMB and miRNA-150 knockout has chondroprotective effects in post-traumatic OA.
In conclusion, GPNMB is highly expressed in damaged compared to the
undamaged cartilage. GPNMB has an anti-inflammatory effect by inhibiting expression of
MMP-3, MMP-9, MMP-13, and ADAMTS4, and IL-6 which induced by IL-1ß. Also, posttraumatic
OA model (DMM) showed that GPNMB is essential to reduce inflammation. Our
results determined that mice lack GPNMB has more cartilage damaged compared to the
WT mice. Also, CD44 knockout mice showed a severe cartilage damage compared to
WT mice while miRNA-150 knockout mice have less cartilage damage. All these results
indicate that extracellular domain of GPNMB has an essential role during cartilage
inflammation in both in vivo and in vitro.
Overall, the extracellular domain of GPNMB may be used as a therapeutic
approach in osteoarthritis and may replace the anti-inflammatory medicine that causes
several side effects which include elevated blood pressure, gastrointestinal bleeding, and
kidney disorders. Also, miRNA-150 inhibitors may also be used as an alternative
therapeutic approach in osteoarthritis.Our future studies will be included: first, the cross-talks between GPNMB and
synovium macrophages and fibroblast in osteoarthritis. Seconds, the crosstalk between
GPNMB and osteoblast and osteoclast cells in subchondral bone remodeling. Third,
monitoring of CD44 phenotype with age-related osteoarthritis. Fourth, miRNA-150 KO,
DBA/2J and DBA/2J GPNMB+ phenotype with age-related osteoarthritis. Fifth, GPNMB
and signaling pathways in osteoarthritis and this will be involved studying signaling
pathways intensely. Sixth, evaluating function of GPNMB in GPNMB transgenic mice
model OA-TG and in GPNMB knockout mice model also study age-related osteoarthritis
in these models. In addition, our future studies will be focused on the treatment option
which involves the administration ways to deliver recombinant extracellular GPNMB
locally by direct injection to the joint. Moreover, future studies will involve the doses and
half-life of GPNMB and also will involve the carrier of GPNMB and study if the
nanoparticles can be used as GPNMB carrier for injection. Also, will study GPNMB as a
therapeutic approach and compare it to hyaluronan treatment since hyaluronan is being
used as a therapeutic option by direct injection to the affected joint.