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Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction
J S Mudgett1, N I Hutchinson, N A Chartrain
1Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Objective:
It has long been proposed that stromelysin is one of the major degradative matrix metalloproteinases responsible for the loss of cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA). This hypothesis was tested by examining the arthritic paws of stromelysin 1 (SLN1)-deficient mice for loss of cartilage and for generation of neoepitopes that would be indicative of aggrecan cleavage.
Methods:
The SLN1 gene was inactivated in murine embryonic stem cells, and knockout mice deficient in SLN1 activity were bred onto the B10.RIII background. The incidence and severity of collagen-induced arthritis (CIA) were compared in wild-type and knockout mice. Paws from mice with CIA were examined for loss of cartilage and for proteoglycan staining, as well as for the generation of the neoepitope FVDIPEN341.
Results:
SLN1-deficient mice developed CIA, as did the wild-type N2 mice. Histologic analyses demonstrated no significant differences among the B10.RIII, wild-type, and knockout mice in loss of articular cartilage and proteoglycan staining. No decrease in the FVDIPEN341 epitope was observed in the SLN1-deficient mice.
Conclusion:
Disruption of the SLN1 gene neither prevents nor reduces the cartilage destruction associated with CIA. Moreover, SLN1 depletion does not prevent the cleavage of the aggrecan Asn341-Phe342 bond.
Insights
Stromelysin 1 (SLN1) deficiency did not prevent cartilage loss in mice with collagen-induced arthritis (CIA). This indicates SLN1 is not a primary driver of cartilage destruction in this arthritis model.
Area of Science:
- Biochemistry
- Immunology
- Rheumatology
Background:
- Matrix metalloproteinases (MMPs), including stromelysin 1 (SLN1), are implicated in cartilage degradation in rheumatoid arthritis (RA) and osteoarthritis (OA).
- The specific role of SLN1 in the pathogenesis of arthritis remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of stromelysin 1 (SLN1) in cartilage destruction in a mouse model of arthritis.
- To determine if SLN1 deficiency impacts the development and severity of collagen-induced arthritis (CIA).
Main Methods:
- Generated SLN1-deficient (knockout) mice by inactivating the SLN1 gene in embryonic stem cells.
- Compared the incidence and severity of collagen-induced arthritis (CIA) in SLN1-deficient and wild-type mice.
- Assessed cartilage loss, proteoglycan staining, and aggrecan neoepitope generation (FVDIPEN341) in arthritic paws.
Main Results:
- SLN1-deficient mice developed collagen-induced arthritis (CIA) similarly to wild-type mice.
- No significant differences were observed in articular cartilage loss or proteoglycan staining between SLN1-deficient and wild-type mice.
- The aggrecan neoepitope FVDIPEN341 was generated in SLN1-deficient mice, indicating aggrecan cleavage still occurred.
Conclusions:
- Disruption of the SLN1 gene does not prevent or reduce cartilage destruction in collagen-induced arthritis (CIA).
- SLN1 is not essential for the cleavage of the aggrecan Asn341-Phe342 bond during CIA.
- These findings suggest SLN1 is not a major contributor to cartilage degradation in this arthritis model.