Orthopedic Research Laboratories, Department of Orthopedic Surgery, Boston Children's Hospital, Boston, MA, USA.
Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA.
Bone. 2020 Feb;131:115084. doi: 10.1016/j.bone.2019.115084. Epub 2019 Oct 21.
Enhancing LRP5 signaling and inhibiting TGFβ signaling have each been reported to increase bone mass and improve bone strength in wild-type mice. Monotherapy targeting LRP5 signaling, or TGFβ signaling, also improved bone properties in mouse models of Osteogenesis Imperfecta (OI). We investigated whether additive or synergistic increases in bone properties would be attained if enhanced LRP5 signaling was combined with TGFβ inhibition. We crossed an Lrp5 high bone mass (HBM) allele (Lrp5) into the Col1a2 mouse model of OI. At 6-weeks-of-age we began treating mice with an antibody that inhibits TGFβ1, β2, and β3 (mAb 1D11), or with an isotype-matched control antibody (mAb 13C4). At 12-weeks-old, we observed that combining enhanced LRP5 signaling with inhibited TGFβ signaling produced an additive effect on femoral and vertebral trabecular bone volumes, but not on cortical bone volumes. Although enhanced LRP5 signaling increased femur strength in a 3-point bending assay in Col1a2 mice, femur strength did not improve further with TGFβ inhibition. Neither enhanced LRP5 signaling nor TGFβ inhibition, alone or in combination, improved femur 3-point-bending post-yield displacement in Col1a2 mice. These pre-clinical studies indicate combination therapies that target LRP5 and TGFβ signaling should increase trabecular bone mass in patients with OI more than targeting either signaling pathway alone. Whether additive increases in trabecular bone mass will occur in, and clinically benefit, patients with OI needs to be determined.
增强 LRP5 信号和抑制 TGFβ 信号都已被报道可增加野生型小鼠的骨量并改善骨强度。靶向 LRP5 信号或 TGFβ 信号的单药治疗也改善了成骨不全症（OI）小鼠模型的骨骼特性。我们研究了如果增强 LRP5 信号与 TGFβ 抑制相结合，是否会获得骨骼特性的相加或协同增加。我们将 Lrp5 高骨量（HBM）等位基因（Lrp5）与 Col1a2 OI 小鼠模型杂交。在 6 周龄时，我们开始用抑制 TGFβ1、β2 和 β3 的抗体（mAb 1D11）或同种型匹配的对照抗体（mAb 13C4）治疗小鼠。在 12 周龄时，我们观察到增强 LRP5 信号与抑制 TGFβ 信号相结合对股骨和椎体小梁骨体积产生了相加作用，但对皮质骨体积没有作用。虽然增强 LRP5 信号增加了 Col1a2 小鼠三点弯曲试验中的股骨强度，但 TGFβ 抑制并未进一步改善股骨强度。单独或联合增强 LRP5 信号或 TGFβ 抑制均未改善 Col1a2 小鼠股骨三点弯曲屈服后位移。这些临床前研究表明，靶向 LRP5 和 TGFβ 信号的联合治疗应比单独靶向任一信号通路更能增加 OI 患者的小梁骨量。在 OI 患者中，是否会发生小梁骨量的相加增加以及是否会带来临床益处，仍需进一步确定。
