Abstract
The generation of cartilage from progenitor cells for the purpose of cartilage repair is often hampered by hypertrophic differentiation of the engineered cartilaginous tissue caused by endochondral ossification. Since a healthy cartilage matrix contains high amounts of Aggrecan and COMP, we hypothesized that their supplementation in the biogel used in the generation of subperiosteal cartilage mimics the composition of the cartilage extracellular matrix environment, with beneficial properties for the engineered cartilage. Supplementation of COMP or Aggrecan was studied in vitro during chondrogenic differentiation of rabbit periosteum cells and periosteum-derived chondrocytes. Low melting agarose was supplemented with bovine Aggrecan, human recombinant COMP or vehicle and was injected between the bone and periosteum at the upper medial side of the tibia of New Zealand white rabbits. Generated subperiosteal cartilage tissue was analyzed for weight, GAG and DNA content and ALP activity. Key markers of different phases of endochondral ossification were measured by RT-qPCR. For the in vitro experiments, no significant differences in chondrogenic marker expression were detected following COMP or Aggrecan supplementation, while in vivo favorable chondrogenic marker expression was detected. Gene expression levels of hypertrophic markers as well as ALP activity were significantly decreased in the Aggrecan and COMP supplemented conditions compared to controls. The wet weight and GAG content of the in vivo generated subperiosteal cartilage tissue was not significantly different between groups. Data demonstrate the potential of Aggrecan and COMP to favorably influence the subperiosteal microenvironment for the in vivo generation of cartilage for the optimization of cartilage regenerative approaches.
Highlights
Cartilage lesions can be debilitating, and are a high-risk factor for the development of osteoarthritis (OA) over time (Mollenhauer and Erdmann, 2002)
We showed in three independent models that chondrogenic differentiation and cartilage homeostasis of periosteal cells in vitro and in vivo can be sustained by the supplementation of Aggrecan or COMP
We hypothesized that the addition of Aggrecan to the in vitro cultures of differentiating periosteal cells, in vivo bioreactor (IVB)-derived chondrocytes and eventually the IVBgenerated cartilage tissue, would increase the chondrogenic differentiation capacity of these cells
Summary
Cartilage lesions can be debilitating, and are a high-risk factor for the development of osteoarthritis (OA) over time (Mollenhauer and Erdmann, 2002). We proposed a novel paradigm for de novo engineering of cartilaginous tissues, the in vivo bioreactor (IVB) This is an alternative cartilage repair concept that we aim to further develop (Emans et al, 2010). We discovered that local subperiosteal application of an agarose biogel provokes a similar cartilage callus-forming process within the created subperiosteal space, without the need of a fracture (Emans et al, 2010). This cartilaginous tissue presents all the hallmarks of hyaline cartilage, and upon transplantation, can heal an osteochondral defect out to 9 months in a rabbit model (Emans et al, 2010). Without further optimization IVB-generated cartilage tissue is prone to further differentiate into hypertrophic cartilage, leading to unwanted ossification
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