Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype

Marjolein M. J. Caron; Ellen G. J. Ripmeester; Guus van den Akker; Nina K. A. P. Wijnands; Jessica Steijns; Don A. M. Surtel; Andy Cremers; Pieter J. Emans; Lodewijk W. van Rhijn; Tim J. M. Welting

doi:10.1016/j.omtm.2021.03.009

Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype

Marjolein M. J. Caron, Ellen G. J. Ripmeester, Guus van den Akker, Nina K. A. P. Wijnands, Jessica Steijns, Don A. M. Surtel, Andy Cremers, Pieter J. Emans, Lodewijk W. van Rhijn, Tim J. M. Welting^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	247-261
Number of pages	15
Journal	Molecular Therapy - Methods and Clinical Development
Volume	21
DOIs	https://doi.org/10.1016/j.omtm.2021.03.009
Publication status	Published - 11 Jun 2021

Keywords

GENE-EXPRESSION
SYNOVIAL-FLUID
CHONDROGENIC DIFFERENTIATION
HYPERTROPHIC DIFFERENTIATION
ARTICULAR CHONDROCYTES
CARTILAGE REPAIR
PROGENITOR CELLS
PROGRESSION
BMP7
RAT

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Caron, M. M. J., Ripmeester, E. G. J., van den Akker, G., Wijnands, N. K. A. P., Steijns, J., Surtel, D. A. M., Cremers, A., Emans, P. J., van Rhijn, L. W., & Welting, T. J. M. (2021). Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype. Molecular Therapy - Methods and Clinical Development, 21, 247-261. https://doi.org/10.1016/j.omtm.2021.03.009

@article{88752ebd51614434a43e51d3052630a8,

title = "Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype",

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.",

keywords = "GENE-EXPRESSION, SYNOVIAL-FLUID, CHONDROGENIC DIFFERENTIATION, HYPERTROPHIC DIFFERENTIATION, ARTICULAR CHONDROCYTES, CARTILAGE REPAIR, PROGENITOR CELLS, PROGRESSION, BMP7, RAT",

author = "Caron, {Marjolein M. J.} and Ripmeester, {Ellen G. J.} and {van den Akker}, Guus and Wijnands, {Nina K. A. P.} and Jessica Steijns and Surtel, {Don A. M.} and Andy Cremers and Emans, {Pieter J.} and {van Rhijn}, {Lodewijk W.} and Welting, {Tim J. M.}",

note = "Funding Information: The authors thank Eke van Zwol for her contributions to Figure 6 . This work was financially supported by grants from the Dutch Arthritis Association ( 13-2-201 , 15-3-403 , and LLP14 ) and Stichting De Weijerhorst . Funding Information: The authors thank Eke van Zwol for her contributions to Figure 6. This work was financially supported by grants from the Dutch Arthritis Association (13-2-201, 15-3-403, and LLP14) and Stichting De Weijerhorst. Substantial contributions to research design, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. L.W.v.R. P.J.E. and T.J.M.W.; substantial contributions to the acquisition of samples, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. and T.J.M.W.; substantial contributions to analysis, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. and T.J.M.W.; substantial contributions to the interpretation of data, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. P.J.E. L.W.v.R. and T.J.M.W.; drafting the paper, M.M.J.C. E.G.J.R. G.v.d.A. and T.J.M.W.; revising paper critically, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. P.J.E. L.W.v.R. and T.J.M.W.; approval of the submitted and final versions, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. P.J.E. L.W.v.R. and T.J.M.W. All authors have read and approved the final submitted manuscript. The study sponsors had no involvement in study design, collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. M.M.J.C. and T.J.M.W. are inventors on patents WO2017178251 and WO2017178253 (owned by Chondropeptix). P.J.E. L.W.v.R. and T.J.M.W. are shareholders in Chondropeptix and are CMO, CDO, and CSO of Chondropeptix, respectively. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jun,

day = "11",

doi = "10.1016/j.omtm.2021.03.009",

language = "English",

volume = "21",

pages = "247--261",

journal = "Molecular Therapy - Methods and Clinical Development",

issn = "2329-0501",

publisher = "Cell Press",

}

Caron, MMJ, Ripmeester, EGJ, van den Akker, G, Wijnands, NKAP, Steijns, J, Surtel, DAM , Cremers, A , Emans, PJ , van Rhijn, LW & Welting, TJM 2021, 'Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype', Molecular Therapy - Methods and Clinical Development, vol. 21, pp. 247-261. https://doi.org/10.1016/j.omtm.2021.03.009

Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype. / Caron, Marjolein M. J.; Ripmeester, Ellen G. J.; van den Akker, Guus et al.
In: Molecular Therapy - Methods and Clinical Development, Vol. 21, 11.06.2021, p. 247-261.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype

AU - Caron, Marjolein M. J.

AU - Ripmeester, Ellen G. J.

AU - van den Akker, Guus

AU - Wijnands, Nina K. A. P.

AU - Steijns, Jessica

AU - Surtel, Don A. M.

AU - Cremers, Andy

AU - Emans, Pieter J.

AU - van Rhijn, Lodewijk W.

AU - Welting, Tim J. M.

N1 - Funding Information: The authors thank Eke van Zwol for her contributions to Figure 6 . This work was financially supported by grants from the Dutch Arthritis Association ( 13-2-201 , 15-3-403 , and LLP14 ) and Stichting De Weijerhorst . Funding Information: The authors thank Eke van Zwol for her contributions to Figure 6. This work was financially supported by grants from the Dutch Arthritis Association (13-2-201, 15-3-403, and LLP14) and Stichting De Weijerhorst. Substantial contributions to research design, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. L.W.v.R. P.J.E. and T.J.M.W.; substantial contributions to the acquisition of samples, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. and T.J.M.W.; substantial contributions to analysis, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. and T.J.M.W.; substantial contributions to the interpretation of data, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. P.J.E. L.W.v.R. and T.J.M.W.; drafting the paper, M.M.J.C. E.G.J.R. G.v.d.A. and T.J.M.W.; revising paper critically, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. P.J.E. L.W.v.R. and T.J.M.W.; approval of the submitted and final versions, M.M.J.C. E.G.J.R. G.v.d.A. N.K.A.P.W. J.S. D.A.M.S. A.C. P.J.E. L.W.v.R. and T.J.M.W. All authors have read and approved the final submitted manuscript. The study sponsors had no involvement in study design, collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. M.M.J.C. and T.J.M.W. are inventors on patents WO2017178251 and WO2017178253 (owned by Chondropeptix). P.J.E. L.W.v.R. and T.J.M.W. are shareholders in Chondropeptix and are CMO, CDO, and CSO of Chondropeptix, respectively. The other authors declare no competing interests. Publisher Copyright: © 2021 The Authors

PY - 2021/6/11

Y1 - 2021/6/11

N2 - 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.

AB - 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.

KW - GENE-EXPRESSION

KW - SYNOVIAL-FLUID

KW - CHONDROGENIC DIFFERENTIATION

KW - HYPERTROPHIC DIFFERENTIATION

KW - ARTICULAR CHONDROCYTES

KW - CARTILAGE REPAIR

KW - PROGENITOR CELLS

KW - PROGRESSION

KW - BMP7

KW - RAT

U2 - 10.1016/j.omtm.2021.03.009

DO - 10.1016/j.omtm.2021.03.009

M3 - Article

C2 - 33850953

SN - 2329-0501

VL - 21

SP - 247

EP - 261

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

ER -

Discovery of bone morphogenetic protein 7-derived peptide sequences that attenuate the human osteoarthritic chondrocyte phenotype

Abstract

Keywords

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