Jacobsen Christina M, Barber Lauren A, Ayturk Ugur M, Roberts Heather J, Deal Lauren E, Schwartz Marissa A, Weis MaryAnn, Eyre David, Zurakowski David, Robling Alexander G, Warman Matthew L
Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, USA; Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA; Division of Genetics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
J Bone Miner Res. 2014 Oct;29(10):2297-306. doi: 10.1002/jbmr.2198.
The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5(p.A214V) ) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5(+/p.A214V) mice to Col1a2(+/p.G610C) mice, which model human type IV OI. We found that Col1a2(+/p.G610C) ;Lrp5(+/p.A214V) offspring had significantly increased bone mass and strength compared to Col1a2(+/p.G610C) ;Lrp5(+/+) littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2(+/p.G610C) mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI.
细胞表面受体低密度脂蛋白受体相关蛋白5（LRP5）是骨量和骨强度的关键调节因子。LRP5中的杂合错义突变通过减少内源性抑制剂（如硬化蛋白（SOST））与LRP5的结合，导致人类常染色体显性高骨量（HBM）。与导致人类HBM突变同源的敲入等位基因（Lrp5(p.A214V)）的杂合小鼠骨量和强度增加。成骨不全症（OI）是一种主要由影响I型胶原蛋白的突变引起的骨骼脆性疾病。我们测试了LRP5途径是否可用于改善OI动物模型的骨骼特性。首先，我们将Lrp5(+/p.A214V)小鼠与Col1a2(+/p.G610C)小鼠交配，后者模拟人类IV型OI。我们发现，与Col1a2(+/p.G610C) ;Lrp5(+/+)同窝小鼠相比，Col1a2(+/p.G610C) ;Lrp5(+/p.A214V)后代的骨量和强度显著增加。改善的骨骼特性不是I型胶原蛋白或其伴侣分子mRNA表达改变的结果，也不是由于突变型I型胶原蛋白分泌的变化。其次，我们用一种抑制硬化蛋白活性的单克隆抗体（Scl-Ab）治疗Col1a2(+/p.G610C)小鼠。我们发现，与用赋形剂治疗的同窝小鼠相比，抗体治疗的小鼠骨量和强度显著增加。这些发现表明，即使不改变骨胶原组成，增加骨形成也可能使OI患者受益。
