Abstract
Joint trauma results in the production of inflammatory cytokines that stimulate the secretion of catabolic enzymes, which degrade articular cartilage. Molecular fragments of the degraded articular cartilage further stimulate inflammatory cytokine production, with this process eventually resulting in post-traumatic osteoarthritis (PTOA). The loss of matrix component aggrecan occurs early in the progression of PTOA and results in the loss of compressive stiffness in articular cartilage. Aggrecan is highly sulfated, associates with hyaluronic acid (HA), and supports the compressive stiffness in cartilage. Presented here, we conjugated the HA-binding peptide GAHWQFNALTVRGSG (GAH) to anionic nanoparticles (hNPs). Nanoparticles conjugated with roughly 19 GAH peptides, termed 19 GAH-hNP, bound to HA in solution and increased the dynamic viscosity by 94.1% compared to an HA solution treated with unconjugated hNPs. Moreover, treating aggrecan-depleted (AD) cartilage explants with 0.10 mg of 19 GAH-hNP restored the cartilage compressive stiffness to healthy levels six days after a single nanoparticle treatment. Treatment of AD cartilage with 0.10 mg of 19 GAH-hNP inhibited the degradation of articular cartilage. Treated AD cartilage had 409% more collagen type II and 598% more GAG content than untreated-AD explants. The 19 GAH-hNP therapeutic slowed ECM degradation in AD cartilage explants, restored the compressive stiffness of damaged cartilage, and showed promise as a localized treatment for PTOA.
Highlights
Post traumatic osteoarthritis (PTOA) accounts for 12.5% of the over 32.5 million cases of osteoarthritis (OA) within the United States [1]
Nanoparticles incubated with GAH in the absence of DMTMM did not result in peptide conjugation to the nanoparticle as determined by results that showed only minor adsorption readings, indicative of the peptide, following NP purification
Increasing the molar equivalent of the GAH-peptide to acrylic acid (AAc) polymerized into the poly(NIPAM-coAMPS-AAc-Bis(acryloyl) cystamine (BAC)) and poly(NIPAM-co-AMPS-AAc-BAC-RBITC) particles led to increased peptide concentration on the hollow nanoparticle (hNP) and hNPsRBITCs, respectively
Summary
Post traumatic osteoarthritis (PTOA) accounts for 12.5% of the over 32.5 million cases of osteoarthritis (OA) within the United States [1]. PTOA is characterized by inflammation of the joint and degradation of articular cartilage [2]. The extracellular matrix (ECM) of cartilage is primarily composed of proteoglycans (4–7% wet weight) and collagen type II (15–22% wet weight), and their interactions significantly control the biology of cartilage [3]. The most abundant proteoglycan in articular cartilage is aggrecan, which is composed of a core protein with covalently bonded sulfated glycosaminoglycan (GAG) chains. The sulfated GAG chains within aggrecan provide a high density of anionic charge, generating an osmotic gradient and enabling cartilage to retain water. This gives articular cartilage its compressive stiffness [4].
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