Abstract
The gene encoding the proteoglycan aggrecan (Agc1) is abundantly expressed in cartilage during development and adulthood, and the loss or diminished deposition of the protein results in a wide range of skeletal malformations. Furthermore, aggrecan degradation is a hallmark of cartilage degeneration occurring in osteoarthritis. In the present study, we investigated the consequences of a partial loss of aggrecan in the postnatal skeleton and in the articular cartilage of adult mice. We took advantage of the previously described Agc1tm(IRES-CreERT2) mouse line, which allows for conditional and timely-regulated deletion of floxed, cartilage-expressed genes. As previously reported, the introduction of the CreERT2 cassette in the 3’UTR causes a disruption of the normal expression of Agc1 resulting in a hypomorphic deposition of the protein. In homozygous mice, we observed a dwarf phenotype, which persisted throughout adulthood supporting the evidence that reduced aggrecan amount impairs skeletal growth. Homozygous mice exhibited reduced proteoglycan staining of the articular cartilage at 6 and 12 months of age, increased stiffening of the extracellular matrix at six months, and developed severe cartilage erosion by 12 months. The osteoarthritis in the hypomorph mice was not accompanied by increased expression of catabolic enzymes and matrix degradation neoepitopes. These findings suggest that the degeneration found in homozygous mice is likely due to the compromised mechanical properties of the cartilage tissue upon aggrecan reduction.
Highlights
Osteoarthritis (OA) is a degenerative disorder of the synovial joints causing significant disability and morbidity in the aging population
Applying nanoscale indentation-type atomic force microscopy (IT-AFM) to characterize cartilage biomechanics, we demonstrated that Agc1CreERT2/CreERT2 mice have stiffer cartilaginous extracellular matrix (ECM) in the superficial, middle and deep zones of the articular cartilage (AC) compared to control and heterozygous mice
These dominant mutations lead to spondyloepiphyseal dysplasia (SED) Kimberly type characterized by proportionate short stature and severe premature osteoarthritis [32] or idiopathic short stature associated with early-onset OA [12,33]
Summary
Osteoarthritis (OA) is a degenerative disorder of the synovial joints causing significant disability and morbidity in the aging population. OA is the most common cause of disability in elderly with an estimated prevalence of 10–15% of adults aged over 60. Genetic and numerous environmental risk factors (e.g., obesity, trauma, joint overuse) are responsible for the etiology of OA. It is generally accepted that uncontrolled homeostasis of the extracellular matrix (ECM) produced by chondrocytes is critical for the onset of the condition. Changes in the composition and structural organization of cartilage ECM proteins may activate catabolic processes degrading proteoglycans and the heterotypic collagen II/IX/XI fibrils, which in turn alter the biomechanical properties of the tissue compromising the correct function of articular cartilage (AC), laying the foundations for the establishment of the disorder
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
