TY - JOUR
T1 - Cartilage-derived retinoic acid-sensitive protein (CD-RAP)
T2 - A stage-specific biomarker of heterotopic endochondral ossification (HEO) in fibrodysplasia ossificans progressiva (FOP)
AU - Lindborg, Carter M.
AU - Brennan, Tracy A.
AU - Wang, Haitao
AU - Kaplan, Frederick S.
AU - Pignolo, Robert J.
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/4
Y1 - 2018/4
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.
AB - 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.
KW - ACVR1
KW - Biomarker
KW - Cartilage-derived retinoic acid-sensitive protein (CD-RAP)
KW - Fibrodysplasia ossificans progressiva (FOP)
KW - Heterotopic ossification
KW - RARγ agonists
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U2 - 10.1016/j.bone.2017.09.016
DO - 10.1016/j.bone.2017.09.016
M3 - Article
C2 - 28963080
AN - SCOPUS:85030721925
SN - 8756-3282
VL - 109
SP - 153
EP - 157
JO - Bone
JF - Bone
ER -