Circulating osteogenic cells in aging and disease

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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.