CK2.1, a bone morphogenetic protein receptor type Ia mimetic peptide, repairs cartilage in mice with destabilized medial meniscus

Abstract

BackgroundOsteoarthritis (OA) of the knee involves degeneration of articular cartilage of the diarthrodial joints. Current treatment options temporarily relieve the joint pain but do not restore the lost cartilage. We recently designed a novel bone morphogenetic protein receptor type I (BMPRI) mimetic peptide, CK2.1, that activates BMPRIa signaling in the absence of bone morphogenetic protein (BMP). Our previous research demonstrated that CK2.1 induced chondrogenesis in vitro and in vivo; however, it is unknown if CK2.1 restores damaged articular cartilage in vivo. In this study, we demonstrate that CK2.1 induced articular cartilage (AC) repair in an OA mouse model.MethodsWe designed hyaluronic acid (HA)-based hydrogel particles (HGPs) that slowly release CK2.1. HGP-CK2.1 particles were tested for chondrogenic potency on pluripotent mesenchymal stem cells (C3H10T1/2 cells) and locally injected into the intra-articular capsule in mice with cartilage defects. C57BL/6J mice were operated on to destabilize the medial meniscus and these mice were kept for 6 weeks after surgery to sustain OA-like damage. Mice were then injected via the intra-articular capsule with HGP-CK2.1; 4 weeks after injection the mice were sacrificed and their femurs were analyzed for cartilage defects.ResultsImmunohistochemical analysis of the cartilage demonstrated complete repair of the AC compared to sham-operated mice. Immunofluorescence analysis revealed collagen type IX production along with collagen type II in the AC of mice injected with HGP-CK2.1. Mice injected with phosphate-buffered saline (PBS) and HGP alone had greater collagen type X and osteocalcin production, in sharp contrast to those injected with HGP-CK2.1, indicating increased chondrocyte hypertrophy.ConclusionsOur results demonstrate that the slow release HGP-CK2.1 drives cartilage repair without the induction of chondrocyte hypertrophy. The peptide CK2.1 could be a powerful tool in understanding the signaling pathways contributing to the repair process, and also may be used as a potential therapeutic for treating degenerative cartilage diseases such as OA.

MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1

“…A 12 h light/dark cycle was maintained in the animal housing rooms. C57Bl/6J mice were transected by the medial meniscotibial ligament and the medial collateral ligament in the right knee ( 19 ). The left knee was not subjected to surgery and used as a control.…”

Chondroinductive/chondroconductive peptides and their-functionalized biomaterials for cartilage tissue engineering

“…Furthermore, the potency of CK2.1 (100 nM) in increasing the protein expression of collagen II (5.3 folds) is significantly higher than BMP-2 (3.0 folds). An advantageous property of CK2.1 over BMP-2 is that it does not lead to hypertrophy or mineralization, which is evidenced by no induction of collagen X and osteocalcin expression by CK2.1 [ 99 , 100 ]. When injected into the tail vein and knee cartilage defects of C57BL/6J mice [ 99 , 100 ], CK2.1 significantly increases cartilage width, collagen II and IX expression in femoral articular cartilage, but not collagen X or trabecular bone mineral density.…”

“…An advantageous property of CK2.1 over BMP-2 is that it does not lead to hypertrophy or mineralization, which is evidenced by no induction of collagen X and osteocalcin expression by CK2.1 [ 99 , 100 ]. When injected into the tail vein and knee cartilage defects of C57BL/6J mice [ 99 , 100 ], CK2.1 significantly increases cartilage width, collagen II and IX expression in femoral articular cartilage, but not collagen X or trabecular bone mineral density. In contrast, BMP-2 significantly enhances cartilage width, collagen X and trabecular bone mineral density, but not collagen II and IX expression [ 99 ] ( Fig.…”

“… Name Biomaterial Method How Ref. CK2.1 Hyaluronic acid (HA)-based hydrogel particles (HGPs) Conjugate Conjugation with the HGPs via Michael addition using cysteine-tagged peptide and acry-lated HGPs [ 100 ] SPPEPS Pentanoate functionalized hyaluronic acid (PHA) Conjugate PHA is conjugated to GCGYGSPPEPS [ 110 ] N-cadherin mimetic peptide KLD-12 hydrogels Self-assembled Not identified [ 41 ] MeHA hydrogels Conjugate N-cadherin mimic peptide (Ac-HAVDIGGGC) with a cysteine residue at the C-terminal end to permit Michael addition with MeHA hydrogels [ 53 ] CMP PEODA Conjugate PEODA conjugated with ACRL–PEG–CMP by photopolymerization of aqueous macromer solution [ 138 ] GFOGER PEG and CMP Conjugate Conjugation with the PEG and CMP peptide via Michael addition [ 43 ] Glycopeptide Glc-PA/E-PA Mix Glycopeptide or peptide amphiphiles are mixed to charged supramolecular gels [ 143 ] PPLG-g-Man/HPPA Conjugate Conjugation of PPLG with HPPA by enzyme-catalyzed crosslinking reaction [ 144 ] RGD Sodium alginate …”

“…100 nM CK2.1 bears an even higher capacity of inducing chondrogenesis in both in-vitro (micromass model) and in-vivo (mice knee cartilage defects) in comparison with 40 nM BMP-2 [ 99 ]. Furthermore, the CK2.1 does not lead to hypertrophy or mineralization [ 99 , 100 ]. Interestingly, in comparison with BMP signaling-derived peptides, only one peptide SPPEPS has been found to adopt or develop peptides from another well-established chondroinductive growth factor TGF-β3.…”