Cartilage-derived retinoic acid-sensitive protein (CD-RAP): A stage-specific biomarker of heterotopic endochondral ossification (HEO) in fibrodysplasia ossificans progressiva (FOP)

Carter M. Lindborg, Tracy A. Brennan, Haitao Wang, Frederick S. Kaplan, Robert Pignolo

Research output: Contribution to journalArticle

Abstract

Background: Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Current drug development for FOP mandates the identification of stage-specific biomarkers to facilitate the evaluation of clinical trial endpoints. Results: Here we show in an injury-induced, constitutively-active transgenic mouse model of FOP that CD-RAP levels peaked between day-7 and day-10 during the zenith of histologically-identified chondrogenesis, preceded radiographically apparent HEO, and were diminished by palovarotene. Cross-sectional analysis of CD-RAP levels in plasma samples from FOP patients demonstrated a statistically non-significant trend toward higher levels in the recent flare-up period (three weeks to three months within onset of symptoms). However, in a longitudinal subgroup analysis of patients followed for at least six months after resolution of flare-up symptoms, there was a statistically significant decrease of CD-RAP when compared to levels in the same patients at the time of active or recent exacerbations. Conclusions: These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP.

Original languageEnglish (US)
Pages (from-to)153-157
Number of pages5
JournalBone
Volume109
DOIs
StatePublished - Apr 1 2018

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Myositis Ossificans
Heterotopic Ossification
Staphylococcal Protein A
Tretinoin
Osteogenesis
Cartilage
Biomarkers
Palovarotene
Proteins
Chondrogenesis
Transgenic Mice
Cross-Sectional Studies
Clinical Trials
Wounds and Injuries
Pharmaceutical Preparations

Keywords

  • ACVR1
  • Biomarker
  • Cartilage-derived retinoic acid-sensitive protein (CD-RAP)
  • Fibrodysplasia ossificans progressiva (FOP)
  • Heterotopic ossification
  • RARγ agonists

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) : A stage-specific biomarker of heterotopic endochondral ossification (HEO) in fibrodysplasia ossificans progressiva (FOP). / Lindborg, Carter M.; Brennan, Tracy A.; Wang, Haitao; Kaplan, Frederick S.; Pignolo, Robert.

In: Bone, Vol. 109, 01.04.2018, p. 153-157.

Research output: Contribution to journalArticle

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abstract = "Background: Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Current drug development for FOP mandates the identification of stage-specific biomarkers to facilitate the evaluation of clinical trial endpoints. Results: Here we show in an injury-induced, constitutively-active transgenic mouse model of FOP that CD-RAP levels peaked between day-7 and day-10 during the zenith of histologically-identified chondrogenesis, preceded radiographically apparent HEO, and were diminished by palovarotene. Cross-sectional analysis of CD-RAP levels in plasma samples from FOP patients demonstrated a statistically non-significant trend toward higher levels in the recent flare-up period (three weeks to three months within onset of symptoms). However, in a longitudinal subgroup analysis of patients followed for at least six months after resolution of flare-up symptoms, there was a statistically significant decrease of CD-RAP when compared to levels in the same patients at the time of active or recent exacerbations. Conclusions: These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP.",
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AU - Pignolo, Robert

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N2 - Background: Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Current drug development for FOP mandates the identification of stage-specific biomarkers to facilitate the evaluation of clinical trial endpoints. Results: Here we show in an injury-induced, constitutively-active transgenic mouse model of FOP that CD-RAP levels peaked between day-7 and day-10 during the zenith of histologically-identified chondrogenesis, preceded radiographically apparent HEO, and were diminished by palovarotene. Cross-sectional analysis of CD-RAP levels in plasma samples from FOP patients demonstrated a statistically non-significant trend toward higher levels in the recent flare-up period (three weeks to three months within onset of symptoms). However, in a longitudinal subgroup analysis of patients followed for at least six months after resolution of flare-up symptoms, there was a statistically significant decrease of CD-RAP when compared to levels in the same patients at the time of active or recent exacerbations. Conclusions: These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP.

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