title: The promotion of osteochondral repair by combined intra-articular injection of parathyroid hormone-related protein and implantation of a bi-layer collagen-silk scaffold.
abstract: The repair of osteochondral defects can be enhanced with scaffolds but is often accompanied with undesirable terminal differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Parathyroid hormone-related protein (PTHrP) has been shown to inhibit aberrant differentiation, but administration at inappropriate time points would have adverse effects on chondrogenesis. This study aims to develop an effective tissue engineering strategy by combining PTHrP and collagen-silk scaffold for osteochondral defect repair. The underlying mechanisms of the synergistic effect of combining PTHrP administration with collagen-silk scaffold implantation for rabbit knee joint osteochondral defect repair were investigated. In vitro studies showed that PTHrP treatment significantly reduced Alizarin Red staining and expression of terminal differentiation-related markers. This is achieved in part through blocking activation of the canonical Wnt/β-catenin signaling pathway. For the in vivo repair study, intra-articular injection of PTHrP was carried out at three different time windows (4-6, 7-9 and 10-12 weeks) together with implantation of a bi-layer collagen-silk scaffold. Defects treated with PTHrP at the 4-6 weeks time window exhibited better regeneration (reconstitution of cartilage and subchondral bone) with minimal terminal differentiation (hypertrophy, ossification and matrix degradation), as well as enhanced chondrogenesis (cell shape, Col2 and GAG accumulation) compared with treatment at other time windows. Furthermore, the timing of PTHrP administration also influenced PTHrP receptor expression, thus affecting the treatment outcome. Our results demonstrated that intra-articular injection of PTHrP at 4-6 weeks post-injury together with collagen-silk scaffold implantation is an effective strategy for inhibiting terminal differentiation and enhancing chondrogenesis, thus improving cartilage repair and regeneration in a rabbit model.
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jialin
authors.initials: J
authors.lastname: Chen
authors.forename: Jiadong
authors.initials: J
authors.lastname: Tao
authors.forename: Changchang
authors.initials: C
authors.lastname: Hu
authors.forename: Longkun
authors.initials: L
authors.lastname: Chen
authors.forename: Hongshi
authors.initials: H
authors.lastname: Zhao
authors.forename: Guowei
authors.initials: G
authors.lastname: Xu
authors.forename: Boon C
authors.initials: BC
authors.lastname: Heng
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Ouyang
mesh_terms: D000368:Aged; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects*; D003094:Collagen / Q000737:chemistry*; D006801:Humans; D008875:Middle Aged; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D047011:Silk / Q000737:chemistry*; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D044162:Parathyroid Hormone-Related Protein; D047011:Silk; D003094:Collagen