Abstract
Treatment of osteoarthritis (OA) is mainly symptomatic by alleviating pain to postpone total joint replacement. Bone morphogenetic protein 7 (BMP7) is a candidate morphogen for experimental OA treatment that favorably alters the chondrocyte and cartilage phenotype. Intra-articular delivery and sustained release of a recombinant growth factor for treating OA are challenging, whereas the use of peptide technology potentially circumvents many of these challenges. In this study, we screened a high-resolution BMP7 peptide library and discovered several overlapping peptide sequences from two regions in BMP7 with nanomolar bioactivity that attenuated the pathological OA chondrocyte phenotype. A single exposure of OA chondrocytes to peptides p[63−82] and p[113−132] ameliorated the OA chondrocyte phenotype for up to 8 days, and peptides were bioactive on chondrocytes in OA synovial fluid. Peptides p[63−82] and p[113−132] required NKX3-2 for their bioactivity on chondrocytes and provoke changes in SMAD signaling activity. The bioactivity of p[63−82] depended on specific evolutionary conserved sequence elements common to BMP family members. Intra-articular injection of a rat medial meniscal tear (MMT) model with peptide p[63−82] attenuated cartilage degeneration. Together, this study identified two regions in BMP7 from which bioactive peptides are able to attenuate the OA chondrocyte phenotype. These BMP7-derived peptides provide potential novel disease-modifying treatment options for OA.
Highlights
Osteoarthritis (OA) is the most common degenerative joint disorder worldwide and presents with degradation of articular cartilage, leading to loss of joint mobility and function, accompanied by chronic pain.[1]
This is defined as reduced expression of collagen type X alpha 1 chain (COL10A1), alkaline phosphatase (ALPL), Runt-related transcription factor 2 (RUNX2), ADAMTS5, MMP13, prostaglandin-endoperoxide synthase 2 or cyclooxygenase-2 (COX-2), and interleukin 6 (IL6) and increased expression of SRY-box transcription factor 9 (SOX9), COL2A1, and NKX3-2
Peptides derived from the central region of Bone morphogenetic protein 7 (BMP7), as well as from the C terminus, exhibited bioactivity that improved the expression of the predefined OA chondrocyte phenotype gene set
Summary
Osteoarthritis (OA) is the most common degenerative joint disorder worldwide and presents with degradation of articular cartilage, leading to loss of joint mobility and function, accompanied by chronic pain.[1]. Challenges that come with intra-articular delivery of a recombinant growth factor for treating OA are its formulation for sustained release from a drug carrier, stability in the hydrolytic and proteolytic OA. Molecular Therapy: Methods & Clinical Development synovial fluid (SF) environment,[18,19,20] and high production costs of the recombinant growth factor. The use of peptide technology potentially circumvents many of the challenges associated with full-length recombinant growth factors.[22] Peptides from BMP7 have previously been reported to support osteogenesis[23,24,25] and prevent fibrosis in acute and chronic kidney injury.[26] Whether peptides derived from BMP7 are able to suppress the pathological OA chondrocyte phenotype[27] was unknown. We postulate that the potential identification of a peptide from BMP7 will hold the future promise to be more compatible, and biochemically modifiable, for incorporation into macromolecular sustained release systems that may potentially be used in the intra-articular treatment of OA
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