Dysregulation of Local Stem/Progenitor Cells as a Common Cellular Mechanism for Heterotopic Ossification

Department of Neurology, Northwestern University Feinberg Medical School, Chicago, Illinois 60611-3008, USA.
Stem Cells (Impact Factor: 6.52). 11/2008; 27(1):150-6. DOI: 10.1634/stemcells.2008-0576
Source: PubMed


Heterotopic ossification (HO), the abnormal formation of true marrow-containing bone within extraskeletal soft tissues, is a serious bony disorder that may be either acquired or hereditary. We utilized an animal model of the genetic disorder fibrodysplasia ossificans progressiva to examine the cellular mechanisms underlying HO. We found that HO in these animals was triggered by soft tissue injuries and that the effects were mediated by macrophages. Spreading of HO beyond the initial injury site was mediated by an abnormal adaptive immune system. These observations suggest that dysregulation of local stem/progenitor cells could be a common cellular mechanism for typical HO irrespective of the signal initiating the bone formation.

Download full-text


Available from: Lixin Kan, Jan 15, 2014
1 Follower
22 Reads
  • Source
    • "muscle and neural lineages. Exp. Cell Res. 314, 1266–1280. doi: 10.1016/j.yexcr. 2008.01.009 Artwohl, M., Lindenmair, A., Roden, M., Waldhausl, W. K., Freudenthaler, A., Klosner, G., et al. (2009). Fatty acids induce apoptosis in human smooth muscle cells depending on chain length, saturation, and duration of exposure. Atherosclerosis 202, 351–362. doi: 10.1016/j.atherosclerosis.2008.05.030 Asakura, A., and Rudnicki, M. A. (2002). Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiati"
    [Show abstract] [Hide abstract]
    ABSTRACT: Pericytes are perivascular cells that envelop and make intimate connections with adjacent capillary endothelial cells. Recent studies show that they may have a profound impact in skeletal muscle regeneration, innervation, vessel formation, fibrosis, fat accumulation, and ectopic bone formation throughout life. In this review, we summarize and evaluate recent advances in our understanding of pericytes' influence on adult skeletal muscle pathophysiology. We also discuss how further elucidating their biology may offer new approaches to the treatment of conditions characterized by muscle wasting.
    Frontiers in Aging Neuroscience 09/2014; 6:245. DOI:10.3389/fnagi.2014.00245 · 4.00 Impact Factor
  • Source
    • "However, when liposomeencapsulated bisphosphonate was locally administered to selectively deplete tissue macrophages in a transgenic mouse model of HO, osteogenesis was significantly blocked. This effect was attributed to the elimination of macrophage-secreted BMP4 at the injury site [24]. In an experimental mouse model of osteoarthritis, macrophage depletion by liposomal bisphosphonate resulted in the reduction of osteophytes (heterotopic bony nodules), which was attributed to reduced macrophage expression of osteogenic TGFb, BMP2, and BMP4. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone graft substitutes such as calcium phosphates are subject to the innate inflammatory reaction, which may bear important consequences for bone regeneration. We speculate that the surface architecture of osteoinductive β-tricalcium phosphate (TCP) stimulates the differentiation of invading monocyte/macrophages into osteoclasts, and that these cells may be essential to ectopic bone formation. To test this, porous TCP cubes with either submicron-scale surface architecture known to induce ectopic bone formation (TCPs, positive control) or micron-scale, non-osteoinductive surface architecture (TCPb, negative control) were subcutaneously implanted on the backs of FVB strain mice for 12 weeks. Additional TCPs samples received local, weekly injections of liposome-encapsulated clodronate (TCPs + LipClod) to deplete invading monocyte/macrophages. TCPs induced osteoclast formation, evident by positive tartrate resistant acid phosphatase (TRAP) cytochemical staining and negative macrophage membrane marker F4/80 immunostaining. No TRAP positive cells were found in TCPb or TCPs + LipClod, only F4/80 positive macrophages and foreign body giant cells. TCPs stimulated subcutaneous bone formation in all implants, while no bone could be found in TCPb or TCPs + LipClod. In agreement, expression of bone and osteoclast gene markers was upregulated in TCPs versus both TCPb and TCPs + LipClod, which were equivalent. In summary, submicron-scale surface structure of TCP induced osteoclastogenesis and ectopic bone formation in a process that is blocked by monocyte/macrophage depletion.
    Biomaterials 06/2014; 35(19):5088–5097. DOI:10.1016/j.biomaterials.2014.03.013 · 8.56 Impact Factor
  • Source
    • "Circulating bone marrow-derived osteogenic precursors are present in human peripheral blood [25], and these cells were suggested to participate in ectopic bone formation in mice and humans [26], [27], [28]. In contrast to these studies, it was also reported that there is no evidence of direct contribution of hematopoietic cells to ectopic bone formation [29], [30]. Furthermore, study of a patient with fibrodysplasia ossificans progressiva, a rare genetic disorder of heterotopic skeletogenesis, who had undergone bone marrow transplantation revealed that cells of hematopoietic origin are not sufficient to form ectopic bone [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterotopic ossification (HO) is defined as the formation of ectopic bone in soft tissue outside the skeletal tissue. HO is thought to result from aberrant differentiation of osteogenic progenitors within skeletal muscle. However, the precise origin of HO is still unclear. Skeletal muscle contains two kinds of progenitor cells, myogenic progenitors and mesenchymal progenitors. Myogenic and mesenchymal progenitors in human skeletal muscle can be identified as CD56 and PDGFRα cells, respectively. The purpose of this study was to investigate the osteogenic differentiation potential of human skeletal muscle-derived progenitors. Both CD56 cells and PDGFRα cells showed comparable osteogenic differentiation potential in vitro. However, in an in vivo ectopic bone formation model, PDGFRα cells formed bone-like tissue and showed successful engraftment, while CD56 cells did not form bone-like tissue and did not adapt to an osteogenic environment. Immunohistological analysis of human HO sample revealed that many PDGFRα cells were localized in proximity to ectopic bone formed in skeletal muscle. MicroRNAs (miRNAs) are known to regulate many biological processes including osteogenic differentiation. We investigated the participation of miRNAs in the osteogenic differentiation of PDGFRα cells by using microarray. We identified miRNAs that had not been known to be involved in osteogenesis but showed dramatic changes during osteogenic differentiation of PDGFRα cells. Upregulation of miR-146b-5p and -424 and downregulation of miR-7 during osteogenic differentiation of PDGFRα cells were confirmed by quantitative real-time RT-PCR. Inhibition of upregulated miRNAs, miR-146b-5p and -424, resulted in the suppression of osteocyte maturation, suggesting that these two miRNAs have the positive role in the osteogenesis of PDGFRα cells. Our results suggest that PDGFRα cells may be the major source of HO and that the newly identified miRNAs may regulate osteogenic differentiation process of PDGFRα cells.
    PLoS ONE 02/2013; 8(2):e56641. DOI:10.1371/journal.pone.0056641 · 3.23 Impact Factor
Show more