Attenuation of Articular Cartilage Degeneration by the Genetic Deletion of HtrA1 in Mice

Abstract

Objective To investigate whether the genetic deletion of the serine protease, high temperature requirement protein A1 (HtrA1), will attenuate the progression of articular cartilage degeneration in mouse osteoarthritis (OA) models. Methods We used two mouse models for our study. The first is a genetic model of OA and includes two strains of mice. The first strain is a heterozygous genetic deletion of type-XI collagen that results in OA in mice (Col11a1+/-). The second strain is a homozygous HtrA1 knockout (HtrA1-/-). By crossing the two strains, we can analyze a possible chondral-protective effect of HtrA1-deficiency on the progression of OA. The second model is a surgical/injury model of OA, in which we performed microsurgery on the knee joints of HtrA1-/- mice to destabilize the medial meniscus (DMM). This technique undermines the joint, and rapidly induces OA in the mice. By surgically inducing osteoarthritis in HtrA1-/- knockout mice, we can simulate the effect of HtrA1-deficiency on the progression of OA due to surgery or injury. Conditions of the articular cartilage from the knee joints of the Col11a1+/-;HtrA1-/- mice, Col11a1+/- mice, HtrA1-/- mice, and the surgical mice were then examined by histology, graded on a standard scoring system, and characterized by immunohistochemistry. Results We examined the HtrA1-/- knockout mice and found no overt phenotype abnormalities. We also found that the deletion of HtrA1 delays the progressive process of articular cartilage degeneration in Col11a1+/- mice. In our surgical model, the degenerative progression towards OA was dramatically delayed in HtrA1-/- mice when compared to the controls. Conclusion Deletion of HtrA1 delays the progression of articular cartilage degeneration in OA models induced either by collagen type-XI haploinsufficiency or by DMM surgery. Therefore, the development of antagonistic drugs that specifically target HTRA1 may be an effective method to treat OA in the future.