Circulating osteogenic cells in aging and disease

描述（由申请人提供）：背景：髋关节相关的病理性骨化，包括终末期钙化性瓣膜病和髋关节置换术后异位骨形成，是老年人群发病率较高的原因。具有成骨潜能的细胞可以在各种组织中发现，并且最近已经在循环中被证明为可以在体内产生骨的单核血液来源的粘附细胞（BdAC）群体。事实上，成骨BdAC可能与循环纤维细胞有关，最初在伤口修复的背景下描述，但随后发现参与肉芽肿形成和各种纤维化疾病。目的：[1]阐明BdAC在骨生成和骨化病理状态中的生理作用。[2]确定BdAC与成骨细胞和成纤维细胞的表型关系。假设：[1]成骨BdAC是来源于骨髓的循环纤维细胞，可以在体外产生矿化基质并在体内形成骨。[2]BdAC参与年龄相关性异位骨化（HO）。具体目的和研究设计：[1]通过表型标志物表征BdAC，以表明BdAC是纤维细胞，并与成骨细胞和成纤维细胞区分开。[2]通过在体外寿命的不同阶段进行的体外矿化和体内骨形成试验，证明BdAC的成骨潜力。[3]通过检测从女性性别不匹配的骨髓移植受者中分离的这些细胞中的Y染色体特异性DNA，确认BdAC作为骨髓的假定组织来源。[4]使用表型标记物的免疫荧光检测终末期钙化性心脏瓣膜病和固定条件下（如髋关节置换术后）发生的HO病变中BdAC的存在。长期替代品：确定BdAC作为成骨细胞的作用，其有可能用于诊断检测、细胞替代疗法或作为基因治疗的靶群体。

DESCRIPTION (provided by applicant): BACKGROUND: Age-related conditions of pathologic ossification, including end-stage calcific valvular disease and ectopic bone formation post-hip arthroplasty, account for great morbidity in the geriatric population. Cells with osteogenic potential can be found in a variety of tissues, and more recently have been demonstrated in the circulation as a population of mononuclear blood-derived adherent cells (BdACs) that can produce bone in vivo. Osteogenic BdACs may, in fact, be related to circulating fibrocytes, initially described in the context of wound repair, but subsequently found to participate in granuloma formation and various fibrosing disorders. OBJECTIVES: [1] To elucidate the physiologic role of BdACs in osteogenesis and in pathological states of ossification. [2] To determine the phenotypic relationship of BdACs to osteoblasts and fibroblasts. HYPOTHESES: [1] Osteogenic BdACs are circulating fibrocytes derived from bone marrow that can produce a mineralized matrix in vitro and form bone in vivo. [2] BdACs are involved in age-related heterotopic ossification (HO). SPECIFIC AIMS and RESEARCH DESIGN: [1] Characterize BdACs by phenotypic markers to show that BdACs are fibrocytes, and distinguishable from osteoblasts and fibroblasts. [2] Demonstrate the osteogenic potential of BdACs by assays of in vitro mineralization and in vivo bone formation performed at various stages of their in vitro life span. [3] Confirm the presumptive tissue origin of BdACs as bone marrow by detecting Y chromosome-specific DNA in these cells isolated from female sex-mismatched bone marrow transplant recipients. [4] Detect the presence of BdACs in lesions of HO occurring in end-stage calcific valvular heart disease and in conditions of immobilization such as post-hip arthroplasty using immunofluorescence of phenotypic markers. LONG-TERM OBJECTIVES: To define the role of BdACs as osteogenic cells with potential for use in diagnostic testing, cell replacement therapy, or as a target population for gene therapy.