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- Title
576. Hypoxic Adipocytes Support Early Heterotopic Bone Formation.
- Authors
Olmsted-Davis, Elizabeth A.; Gannon, Francis H.; Gugala, Zbigniew; Hipp, John A.; Foultier-Dilling, Christine; Heggeness, Michael H.; Davis, Alan R.
- Abstract
The factors contributing to heterotopic ossification, the formation of bone in abnormal soft-tissue locations, are beginning to emerge, but very little is known about the microenvironmental conditions that promote this often devastating disease. Using a murine model in which endochondral bone formation is triggered in muscle by bone morphogenetic protein 2 (BMP2), we studied the cellular and biochemical changes near the site of injection of BMP2- expressing cells. As early as 24 hours after BMP2 stimulation, brown adipocytes began to accumulate in the lesional area. These cells stained positively for pimonidazole and therefore generated hypoxic stress (most likely through uncoupled mitochondrial respiration) within the target tissue, a prerequisite for the differentiation of stem cells to chondrocytes and subsequent heterotopic bone formation. They also expressed the angiogenic growth factor VEGF-D, which is required for normal vascularization and remodeling of the cartilaginous matrix formed by chondrocytes. We propose that aberrant expression of BMPs in soft tissue stimulates the production of brown adipocytes, which drive the early steps of heterotopic ossification by lowering the oxygen tension in adjacent tissue and secreting VEGF-D. Further results, obtained in mutant mice that do not produce brown fat, suggest that white adipocytes can convert to fat-oxidizing cells when brown adipocytes are not available, providing a compensatory mechanism for the generation of a hypoxic microenvironment. Manipulation of the transcriptional control of adipocyte fate in local soft-tissue environments may offer a means to prevent or treat the development of bone in extraskeletal sites.Molecular Therapy (2006) 13, S222–S222; doi: 10.1016/j.ymthe.2006.08.649
- Subjects
FAT cells; GROWTH factors; STEM cells; VITAL signs; BONES
- Publication
Molecular Therapy, 2006, Vol 13, pS222
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2006.08.649