Details

Autor(en) / Beteiligte

• Agarwal, Shailesh
• Loder, Shawn J.
• Brownley, Cameron
• Eboda, Oluwatobi
• Peterson, Jonathan R.
• Hayano, Satoru
• Wu, Bingrou
• Zhao, Bin
• Kaartinen, Vesa
• Wong, Victor C.
• Mishina, Yuji
• Levi, Benjamin

Titel

BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints

Ist Teil von

• Developmental biology, 2015-04, Vol.400 (2), p.202-209

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre+ transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints – tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration. [Display omitted] •ca-ACVR1fx/WT/Nfatc1-Cre+ mice develop heterotopic ossification at joints without trauma.•Heterotopic bone in ca-ACVR1fx/WT/Nfatc1-Cre+ mice occur by endochondral ossification.•ca-ACVR1fx/WT/Nfatc1-Cre+ mouse skeletal bones have similar thickness to littermate controls.•Cells from heterotopic bone are more osteogenic in vitro compared to cells from skeletal bone.•Heterotopic bone in ca-ACVR1fx/WT/Nfatc1-Cre+ mice are enriched with bone progenitor cells.