Details

Autor(en) / Beteiligte

• OMOSULE, CATHERINE LAARIPUOH
• Jeong, Youngjae
• Phillips, Charlotte
• Pfeiffer, Ferris

Titel

Soluble Activin Type IIB Receptor Decoy changes Gene Expression Profiles of Bone Cells in the OIM and not the G610C Mouse Model of Osteogenesis Imperfecta

Ist Teil von

• The FASEB journal, 2018-04, Vol.32 (S1), p.660.5-660.5

Ort / Verlag

The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• Bone is a highly dynamic tissue which is continually remodeled by osteoblasts and osteoclasts, with regulation by osteocytes. In Osteogenesis Imperfecta (OI), a clinically heterogeneous disorder characterized by bone fragility, the functions of osteoblasts and osteoclasts are thought to be impaired. As a mechanosensitive tissue, bone responds to mechanical loads, some of the strongest of which are from skeletal muscles, by changing its shape. The inhibition of myostatin, a negative regulator of muscle growth and a member of the TGF‐β superfamily, has been shown to induce muscle growth via hypertrophy. In this study, we investigated the effect of pharmacologically inhibiting myostatin through treatment with the soluble activin receptor type IIB decoy molecule (sActRIIB‐mFc), focusing on the gene expression patterns of bone cells derived from two molecularly distinct mouse models of OI (osteogenesis imperfecta murine [OIM] vs. G610C). Because the molecular defects that give rise to the G610C and OIM models differ and muscle function is differentially impacted, we hypothesize that the two models may respond differently to sActRIIB‐mFc treatment. Homozygous mice (oim/oim) in the OIM model have a single nucleotide deletion in the COL1A2 gene that leads to functional null proα2 (I) collagen chains and the generation of homotrimeric type I collagen, whereas the G610C mouse, heterozygous for a missense mutation in the COL1A2 gene, has a glycine to cysteine substitution at the 610 position of the triple helical domain. At two months of age, WT, +/G610C, and oim/oim male mice were treated bi‐weekly either with vehicle (Tris‐buffered saline) or sActRIIB‐mFc for 8 weeks. Quantitative RT‐PCR analyses demonstrated that tibias from sActRIIB‐mFc treated oim/oim mice exhibited increased gene expression levels of the markers of osteoblast, osteoclast, and osteocyte function and differentiation analyzed. This contrasts with the significant changes seen in the femoral cortical bone microarchitecture and biomechanical integrity of sActRIIB‐mFc‐treated WT and +/G610C mice, which was not observed in the oim/oim mice. In conclusion, our findings indicate that sActRIIB‐mFc treatment has differential effects on the G610C and OIM mice, which may in part reflect differences in severity (severe in oim/oim vs. moderately severe in +/G610C), and/or their unique molecular defects. Understanding the molecular impact of therapeutics is critical in order to develop more effective and targeted treatment for OI. Support or Funding Information Leda J. Sears TrustKansas City Area life Sciences Institute Patton Trust Research, Inc. University of Missouri Research Board GrantMarch of Dimes This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.