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

• Published in: Bone (New York, N.Y.) Vol. 109; pp. 153 - 157
• Main Authors: Lindborg, Carter M., Brennan, Tracy A., Wang, Haitao, Kaplan, Frederick S., Pignolo, Robert J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2018
• Subjects: ACVR1; Adult; Animals; Biomarker; Biomarkers - metabolism; Cartilage-derived retinoic acid-sensitive protein (CD-RAP); Cross-Sectional Studies; Extracellular Matrix Proteins - metabolism; Female; Fibrodysplasia ossificans progressiva (FOP); Heterotopic ossification; Humans; Male; Mice; Mice, Transgenic; Myositis Ossificans - metabolism; Myositis Ossificans - pathology; Neoplasm Proteins - metabolism; Ossification, Heterotopic - metabolism; Ossification, Heterotopic - pathology; Osteogenesis - physiology; RARγ agonists; Young Adult; ACVR1; Biomarker; Heterotopic ossification; Cartilage-derived retinoic acid-sensitive protein (CD-RAP); RARγ agonists; Fibrodysplasia ossificans progressiva (FOP)
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2017.09.016

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.
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.
These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP.
•Cartilage-derived retinoic acid-sensitive protein (CD-RAP) may be a pre-osseous marker of heterotopic ossification.•In a transgenic mouse model of FOP, CD-RAP levels peaked at the zenith of histologically-identified chondrogenesis.•CD-RAP levels were diminished by palovarotene, a retinoic acid receptor-γ agonist and potent inhibitor of chondrogenesis.•CD-RAP levels in plasma samples from FOP patients were associated with flare-up status.