Article

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

ABSTRACT

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.

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Available from: Lixin Kan, Jan 15, 2014
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    • "It is shown to induce osteogenic differentiation of human mesenchymal cells [32] [33] whereas osteogenic transdifferentiation of fibroblasts with platelet-rich plasma has been demonstrated in mice [34]. Although the culprit cell type responsible for FOP remains elusive, BMP signaling has been suggested to alter stem cell fate [22]. Given the lack of specialized fibroblastspecific markers [35], their ability to differentiate into other cell types [36], the identification of different populations of stem cells in the epidermis [37], and the presence of highly fibroproliferative lesions in FOP patients [20], fibroblasts are appropriate for the study of FOP flare-ups and osteogenic cell differentiation. "
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    ABSTRACT: Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification. FOP patients develop soft tissue lumps as a result of inflammation-induced flare-ups which leads to the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients possess a mutation (c.617G > A; R206H) in the ACVR1-encoding gene which leads to dysregulated BMP signaling. Nonetheless, not all FOP patients with this mutation exhibit equal severity in symptom presentation or disease progression which indicates a strong contribution by environmental factors. Given the pro-inflammatory role of TGFβ, we studied the role of TGFβ in the progression of osteogenic differentiation in primary dermal fibroblasts from five classical FOP patients based on a novel method of platelet lysate-based osteogenic transdifferentiation. During the course of transdifferentiation the osteogenic properties of the cells were evaluated by the mRNA expression of Sp7/Osterix, Runx2, Alp, OC and the presence of mineralization. During transdifferentiation the expression of osteoblast markers Runx2 (p < 0.05) and Alp were higher in patient cells compared to healthy controls. All cell lines exhibited increase in mineralisation. FOP fibroblasts also expressed higher baseline Sp7/Osterix levels (p < 0.05) confirming their higher osteogenic potential. The pharmacological inhibition of TGFβ signaling during osteogenic transdifferentiation resulted in the attenuation of osteogenic transdifferentiation in all cell lines as shown by the decrease in the expression of Runx2 (p < 0.05), Alp and mineralization. We suggest that blocking of TGFβ signaling can decrease the osteogenic transdifferentiation of FOP fibroblasts.
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    • "However, using CD19-Cre, LCK-Cre, and Lyz-Cre transgenic mice, researchers have shown that B cells, T cells, and macrophages/monocytes, respectively, do not generate them (Kan et al., 2009). Somite-derived cells were excluded using Nestin-Cre reporter mice, and myoblasts, which are more committed to the myogenic lineage, were excluded using Myf5-Cre (Kan et al., 2009) and MyoD-Cre (Lounev et al., 2009) transgenic mice. These results are consistent with the fact that, during the generation of ectopic bone, the early immune response in skeletal muscle lesions kills myoblasts (Shore and Kaplan, 2010). "
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    • "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. "
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    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.
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