Studies by University of Birmingham researchers suggest that a naturally occurring peptide known as PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration), could represent a promising potential therapeutic for osteoporosis and other disorders that feature bone loss, and offer distinct advantages compared with existing drugs..

伯明翰大学研究人员的研究表明，一种天然存在的肽称为PEPITEM（跨内皮迁移的肽抑制剂），可能是骨质疏松症和其他以骨质流失为特征的疾病的有希望的潜在治疗方法，并且与现有药物相比具有明显的优势。。

PEPITEM was first identified in 2015 by University of Birmingham researchers. The team’s latest study has shown for the first time that PEPITEM could be used as a novel and early clinical intervention to reverse the impact of age-related musculoskeletal diseases. Their reported study demonstrated that PEPITEM enhances bone mineralization, formation and strength, and reverses bone loss in animal models of disease..

伯明翰大学的研究人员于2015年首次确定了PEPITEM。该团队的最新研究首次表明，PEPITEM可以作为一种新型的早期临床干预措施，以逆转与年龄相关的肌肉骨骼疾病的影响。他们报道的研究表明，PEPITEM可增强骨矿化，形成和强度，并逆转疾病动物模型中的骨质流失。。

Helen McGettrick, PhD, associate professor in inflammation and vascular biology said, “While the most commonly used drugs, bisphosphonates, work by blocking the action of osteoclasts, PEPITEM acts by swinging the balance in favor of bone formation, without impacting the ability of osteoclasts to resorb regions of damaged or weak bone tissue via normal bone remodeling.”.

炎症和血管生物学副教授Helen McGettrick博士说：“虽然最常用的药物双膦酸盐通过阻断破骨细胞的作用而起作用，但PEPITEM通过摆动平衡来促进骨形成，而不会影响破骨细胞通过正常骨重塑再吸收受损或脆弱骨组织区域的能力。”。

McGettrick is senior, and corresponding author of the team’s published paper in Cell Reports Medicine. In their paper, titled “Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss,” the investigators concluded, “… PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.”.

McGettrick是该团队在Cell Reports Medicine上发表的论文的资深通讯作者。在他们题为“骨修复的治疗途径：利用合成代谢骨肽PEPITEM促进骨骼生长和预防骨质流失”的论文中，研究人员得出结论，“PEPITEM为治疗骨质流失过多的疾病提供了另一种治疗选择，促进内源性合成代谢途径诱导骨骼重塑并纠正骨转换的不平衡。”。

Bone is constantly formed, reformed, and remodelled throughout life, and up to 10 percent of human bone is replaced annually through a complex interplay between two cell types— osteoblasts, which form bone, and osteoclasts, which breakdown bone. “Bone is a highly active organ, undergoing continuous osteoblast-induced bone formation and osteoclast-mediated bone resorption throughout life,” the authors explained.

骨骼在整个生命过程中不断形成，改造和重塑，每年多达10%的人类骨骼通过两种细胞类型之间的复杂相互作用而被替换-形成骨骼的成骨细胞和破坏骨骼的破骨细胞。作者解释说：“骨骼是一种高度活跃的器官，在整个生命过程中不断经历成骨细胞诱导的骨形成和破骨细胞介导的骨吸收。”。

“The process of bone remodeling is orchestrated by cross-talk among osteoblasts, osteoclasts, and osteocytes acting in concert to maintain structural integrity, repair damage, and respond to changes in activity and load.”.

“骨重塑的过程是通过成骨细胞，破骨细胞和骨细胞之间的相互作用来协调的，以维持结构完整性，修复损伤，并响应活动和负荷的变化。”。

Disturbances to this tightly orchestrated process are responsible for features of musculoskeletal (MSK) diseases such as osteoporosis, rheumatoid arthritis, and cancer-bone metastases, which show excessive bone breakdown, or ankylosing spondylitis, which is characterized by abnormal bone growth.

对这一紧密协调的过程的干扰是造成肌肉骨骼（MSK）疾病特征的原因，例如骨质疏松症，类风湿性关节炎和癌症骨转移，这些疾病表现出过度的骨破坏，或以异常骨生长为特征的强直性脊柱炎。

Osteoporosis is the most common bone disease globally, affecting over 54 million individuals in the U.S., and accounting for three million broken bones at a cost of $26 billion per annum, the team stated. “There are no cures for bone damage.” The most commonly used osteoporosis therapies (bisphosphonates) target osteoclasts to prevent further bone loss.

该研究小组表示，骨质疏松症是全球最常见的骨病，影响美国5400多万人，每年造成300万人骨折，花费260亿美元。“没有治愈骨损伤的方法。”最常用的骨质疏松症疗法（双膦酸盐）靶向破骨细胞以防止进一步的骨质流失。

Although there are new ‘anabolic’ agents that can promote new bone formation, these have limitations in their clinical use, with teriparatide (parathyroid hormone; PTH) only being effective for 24 months and romosozumab (anti-sclerostin antibody) being associated with cardiovascular events..

尽管有新的“合成代谢”药物可以促进新骨形成，但这些药物在临床应用上存在局限性，特立帕肽（甲状旁腺激素；PTH）仅在24个月内有效，而罗莫珠单抗（抗硬化蛋白抗体）与心血管事件有关。。

There is a clear case for developing new therapies to stimulate bone repair in age-related musculoskeletal diseases, including osteoporosis, the researchers pointed out. “… there is an urgent need to develop a new suite of therapies that lead to bone repair and regeneration in patients with MSK diseases to restore tissue homeostasis and functional integrity.” For their reported work the team—headed by McGettrick and Amy Naylor, PhD, Jonathan Lewis, PhD, and Kathryn Frost, from the Institute of Inflammation and Ageing at the University of Birmingham, and James Edwards, PhD, from Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences at the University of Oxford—set out to investigate the potential therapeutic impact of PEPITEM in these disease states..

研究人员指出，有明确的理由开发新的疗法来刺激与年龄有关的肌肉骨骼疾病（包括骨质疏松症）的骨骼修复。“……迫切需要开发一套新的疗法，使MSK疾病患者的骨骼修复和再生，以恢复组织稳态和功能完整性。”对于他们报告的工作，由伯明翰大学炎症与衰老研究所的McGettrick和Amy Naylor博士，Jonathan Lewis博士和Kathryn Frost博士以及牛津大学纳菲尔德骨科，风湿病和肌肉骨骼科学系的James Edwards博士领导的团队开始研究PEPITEM在这些疾病状态下的潜在治疗效果。。

PEPITEM is a naturally occurring peptide that is produced in the body and circulates at low levels. Through their studies in mice, the team demonstrated that PEPITEM regulates bone remodeling, and that increasing the amount present in the body stimulated bone mineralization in “young bones” that are not in a diseased or pre-osteoporotic state.

PEPITEM是一种天然存在的肽，在体内产生并以低水平循环。通过对小鼠的研究，该团队证明PEPITEM调节骨骼重塑，并且增加体内存在的量会刺激未处于患病或骨质疏松前状态的“年轻骨骼”的骨矿化。

“PEPITEM therapy significantly increased bone volume (BV/TV), trabecular number, and thickness in both the tibia and vertebrae of adult mice, indicating that PEPITEM promotes bone formation.” This, they found, translated to an increase in bone strength and density similar to that promoted by current standard of care drugs (bisphosphonates and PTH).

“PEPITEM疗法显着增加成年小鼠胫骨和椎骨的骨量（BV/TV），小梁数量和厚度，表明PEPITEM促进骨形成。”他们发现，这转化为骨强度和密度的增加，类似于目前标准治疗药物（双膦酸盐和PTH）所促进的。

“… the effect size for PEPITEM on BV/TV at two weeks is comparable to that seen following treatment with the bisphosphonate zoledronic acid for three weeks  or PTH for up to four weeks.Thus indicating PEPITEM is as efficient at inducing bone formation compared with current standard of care,” they noted..

“…PEPITEM在两周时对BV/TV的影响大小与双膦酸盐唑来膦酸治疗三周或PTH治疗长达四周后的效果相当。因此表明PEPITEM在诱导骨形成方面与目前的护理标准一样有效，”他们指出。。

A key test for a potential new therapeutic is its ability to target the natural repair process that is compromised by age, or inflammatory disease. Through their work the researchers showed that PEPITEM administration limited bone loss and improved bone density in ovariectomized animal models of the menopause, which is a common trigger for osteoporotic bone loss in humans.

一种潜在的新疗法的关键测试是其针对受年龄或炎症性疾病影响的自然修复过程的能力。通过他们的工作，研究人员表明，PEPITEM给药可以限制绝经期去卵巢动物模型的骨质流失并改善骨密度，这是人类骨质疏松性骨质流失的常见诱因。

“Crucially, PEPITEM therapy halted any further bone loss following ovariectomy,” they wrote, and was effective at inducing bone formation by osteoblasts isolated from aged donors with osteoarthritis.” Their studies also showed similar findings in models of inflammatory bone disease (arthritis), where PEPITEM significantly reduced bone damage and erosion.

“至关重要的是，PEPITEM疗法阻止了卵巢切除术后进一步的骨质流失，”他们写道，并且有效地诱导了从患有骨关节炎的老年供体中分离出的成骨细胞形成骨。”他们的研究还在炎性骨病（关节炎）模型中显示了类似的发现，其中PEPITEM显着减少了骨损伤和侵蚀。

“Similar findings were seen in an inflammatory model of bone erosion, where PEPITEM treatment significantly reduced bone damage in arthritic mice when compared with vehicle-treated animals.”.

“在骨侵蚀的炎症模型中也发现了类似的发现，与载体治疗的动物相比，PEPITEM治疗显着降低了关节炎小鼠的骨损伤。”。

The findings in mice were supported by the results of work using human bone tissue, harvested from older patients during joint surgery. These studies showed that cells from older individuals respond to PEPITEM, significantly increasing the maturation of osteoblasts, and their ability to produce and mineralise bone tissues..

在老鼠身上的发现得到了使用人类骨组织的研究结果的支持，这些骨组织是在关节手术期间从老年患者身上采集的。这些研究表明，来自老年人的细胞对PEPITEM有反应，显着增加了成骨细胞的成熟，以及它们产生和矿化骨组织的能力。。

The team’s cell and tissue culture work further showed PEPITEM has a direct effect on osteoblasts to promote bone formation, by increasing the activity of osteoblasts rather than their number. Further experiments identified the NCAM-1 receptor as the specific receptor for PEPITEM on osteoblasts, and strongly suggested the NCAM-1- β-catenin signalling pathway is responsible for the upregulation of osteoblast activity.

该团队的细胞和组织培养工作进一步表明，PEPITEM通过增加成骨细胞的活性而不是数量，对成骨细胞具有促进骨形成的直接作用。进一步的实验确定NCAM-1受体是成骨细胞上PEPITEM的特异性受体，并强烈表明NCAM-1-β-连环蛋白信号通路负责成骨细胞活性的上调。

“PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength,” they wrote. This receptor, and the pathway, are distinct from PEPITEM receptors that have been previously described in other tissues..

他们写道：“PEPITEM通过NCAM-1信号传导直接作用于成骨细胞，促进其成熟和新骨的形成，从而增强小梁骨的生长和强度。”。该受体和途径不同于先前在其他组织中描述的PEPITEM受体。。

The researchers also investigated PEPITEM’s effect on osteoclasts and bone resorption.  Here, mouse studies showed that PEPITEM significantly reduces the number of osteoclasts, leading to reduced bone mineral resorption. “Analysis of bone sections from mice treated with PEPITEM revealed a significant reduction in osteoclast numbers when compared with the treatment controls …” The researchers subsequently demonstrated that the reduction in osteoclast activity is the result of a soluble substance, osteoprotegerin (OPG) released locally in bone tissues by osteoblasts ‘activated’ by PEPITEM.

研究人员还研究了PEPITEM对破骨细胞和骨吸收的影响。在这里，小鼠研究表明，PEPITEM显着减少破骨细胞的数量，导致骨矿物质吸收减少。“对用PEPITEM治疗的小鼠的骨切片的分析显示，与治疗对照组相比，破骨细胞数量显着减少……”研究人员随后证明，破骨细胞活性的降低是可溶性物质骨保护素（OPG）在骨组织中被PEPITEM“激活”的成骨细胞局部释放的结果。

The collective data, they stated, “…  indicate that in response to PEPITEM signaling through NCAM-1, osteoblasts release OPG, which in turn negatively regulate osteoclast numbers, leading to an overall reduction in bone resorption and increase in bone density.”.

他们表示，这些集体数据“……表明，响应于通过NCAM-1发出的PEPITEM信号，成骨细胞释放OPG，进而负调节破骨细胞数量，导致骨吸收总体减少和骨密度增加。”。

The study results, the team stated, “… highlight that PEPITEM could be used as an alternative and early clinical intervention to reverse the impact of age-related MSK diseases … As an endogenous osteogenic peptide with the capacity to regulate osteoblast-osteoclast coupling in health and disease, PEPITEM offers the real possibility for maintenance or restoration of bone homeostasis over the long-term to prevent osteoporosis and fragility fractures.

该团队表示，研究结果表明，“……强调PEPITEM可作为替代和早期临床干预措施，以逆转与年龄相关的MSK疾病的影响……作为一种内源性成骨肽，具有调节成骨细胞-破骨细胞在健康和疾病中的耦合的能力，PEPITEM为长期维持或恢复骨稳态以预防骨质疏松症和脆性骨折提供了真正的可能性。

For this to be realized, prolonged treatment protocols are now required in a variety of bone disease models to ascertain the quality of the bone formed in response to PEPITEM therapy.”.

为了实现这一点，现在需要在各种骨病模型中延长治疗方案，以确定响应PEPITEM治疗而形成的骨骼的质量。”。

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