The Anti-Inflammatory Role of GPNMB in Post-Traumatic Osteoarthritis
Curation statements for this article:-
Curated by eLife
eLife Assessment
This study offers useful findings demonstrating the cartilage-protective effects of osteoactivin in inflammatory experimental models. The study provides compelling evidence that osteoactivin may serve as a promising therapeutic target for inflammatory joint diseases.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Abstract
Osteoactivin (GPNMB) is a transmembrane protein expressed in multiple cell types with known functions in muscle, bone, and neurons, but the role of GPNMB in chondrocytes and cartilage homeostasis remains unknown. Here we show GPNMB is expressed in human and mouse primary chondrocytes, and that its expression is increased in damaged human cartilage and under pro-inflammatory conditions. We report that recombinant GPNMB treatment inhibits the expression of Mmps, Adamts-4 and Il-6 following IL-1β-stimulation in vitro. In vivo, GPNMB function was assessed in a post-traumatic osteoarthritis model, destabilization of the medial meniscus (DMM). Transgenic animals lacking functional GPNMB protein (DBA/2J) developed severe cartilage damage and demonstrated significant increases in pro-inflammatory cytokine expression following DMM. To elucidate the mechanism of action, we demonstrate that GPNMB regulates the MAPK signaling pathway in primary murine chondrocytes. Taken together, our results identify a novel anti-inflammatory role for GPNMB in cartilage and chondrocytes and identify GPNMB as a potential therapeutic modality for inflammatory joint diseases.
Article activity feed
-
-
-
eLife Assessment
This study offers useful findings demonstrating the cartilage-protective effects of osteoactivin in inflammatory experimental models. The study provides compelling evidence that osteoactivin may serve as a promising therapeutic target for inflammatory joint diseases.
-
Reviewer #1 (Public review):
Summary:
While previous studies by this group and others have demonstrated the anti-inflammatory properties of osteoactivin, its specific role in cartilage homeostasis and disease pathogenesis remains unknown. Building on current knowledge, Asaad and colleagues investigated the functional role of this protein using both in vitro systems and an in vivo post-traumatic osteoarthritis model. In line with existing literature, the authors report that osteoactivin exerts inhibitory effects in these experimental settings. This study thus offers novel evidence supporting the cartilage-protective effects of osteoactivin in various experimental models.
Strengths:
Strengths of the study include its clinical relevance, given the lack of curative treatments for osteoarthritis, as well as the clarity of the narrative and …
Reviewer #1 (Public review):
Summary:
While previous studies by this group and others have demonstrated the anti-inflammatory properties of osteoactivin, its specific role in cartilage homeostasis and disease pathogenesis remains unknown. Building on current knowledge, Asaad and colleagues investigated the functional role of this protein using both in vitro systems and an in vivo post-traumatic osteoarthritis model. In line with existing literature, the authors report that osteoactivin exerts inhibitory effects in these experimental settings. This study thus offers novel evidence supporting the cartilage-protective effects of osteoactivin in various experimental models.
Strengths:
Strengths of the study include its clinical relevance, given the lack of curative treatments for osteoarthritis, as well as the clarity of the narrative and the quality of most results.
Weaknesses:
A limitation of the study is the reliance on standard techniques; however, this is a minor concern that does not diminish the overall impact or significance of the work.
-
Reviewer #2 (Public review):
Summary:
This manuscript presents compelling evidence for a novel anti-inflammatory function of glycoprotein non-metastatic melanoma protein B (GPNMB) in chondrocyte biology and osteoarthritis (OA) pathology. Through a combination of in vitro, ex vivo, and in vivo models, including the destabilization of the medial meniscus (DMM) surgery in mice, the authors demonstrate that GPNMB expression is upregulated in OA-affected cartilage and that recombinant GPNMB treatment reduces the expression of key catabolic markers (MMPs, Adamts-4, and IL-6) without impairing anabolic gene expression. Notably, DBA/2J mice lacking functional GPNMB exhibit exacerbated cartilage degradation post-injury. Mechanistically, GPNMB appears to mitigate inflammation via the MAPK/ERK pathway. Overall, the work is thorough, …
Reviewer #2 (Public review):
Summary:
This manuscript presents compelling evidence for a novel anti-inflammatory function of glycoprotein non-metastatic melanoma protein B (GPNMB) in chondrocyte biology and osteoarthritis (OA) pathology. Through a combination of in vitro, ex vivo, and in vivo models, including the destabilization of the medial meniscus (DMM) surgery in mice, the authors demonstrate that GPNMB expression is upregulated in OA-affected cartilage and that recombinant GPNMB treatment reduces the expression of key catabolic markers (MMPs, Adamts-4, and IL-6) without impairing anabolic gene expression. Notably, DBA/2J mice lacking functional GPNMB exhibit exacerbated cartilage degradation post-injury. Mechanistically, GPNMB appears to mitigate inflammation via the MAPK/ERK pathway. Overall, the work is thorough, methodologically sound, and significantly advances our understanding of GPNMB as a protective modulator in osteoarthritic joint disease. The findings could open pathways for therapeutic development.
Strengths:
(1) Clear hypothesis addressing a well-defined knowledge gap.
(2) Robust and multi-modal experimental design: includes human, mouse, cell-line, explant, and surgical OA models.
(3) Elegant use of DBA/2J GPNMB-deficient mice to mimic endogenous loss-of-function.
(4) Mechanistic insight provided through MAPK signaling analysis.
(5) Statistical analysis appears rigorous, and figures are informative.
Weaknesses:
(1) Clarify the strain background of the DBA/2J GPNMB+ mice: While DBA/2J GPNMB+ is described as a control, it would help to explicitly state whether these are transgenically rescued mice or another background strain. Are they littermates, congenic, or a separate colony?
(2) Provide exact sample sizes and variance in all figure legends: Some figures (e.g., Figure 2 panels) do not consistently mention how many replicates were used (biological vs. technical) for each experimental group. Standardizing this across all panels would improve reproducibility.
(3) Expand on potential sex differences: The DMM model is applied only in male mice, which is noted in the methods. It would be helpful if the authors added 1-2 lines in the discussion acknowledging potential sex-based differences in OA progression and GPNMB function.
(4) Visual clarity in schematic (Figure 7): The proposed mechanism is helpful, but the text within the schematic is somewhat dense and could be made more readable with spacing or enlarged font. Also, label the MAPK/ERK pathway explicitly in panel B.
-
