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Substance P signaling mediates BMP-dependent heterotopic ossification.

ABSTRACT: Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive bone morphogenetic protein (BMP) signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP4, a mouse model of HO, robust HO forms in response to tissue injury; however, null mutations of the preprotachykinin (PPT) gene encoding SP prevent HO. Importantly, ablation of SP(+) sensory neurons, treatment with an antagonist of SP receptor NK1r, deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibit injury-induced HO. These observations establish a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and identify novel molecular targets for prevention of HO.

SUBMITTER: Kan L

PROVIDER: S-EPMC3508732 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Substance P signaling mediates BMP-dependent heterotopic ossification.

Kan Lixin L Lounev Vitali Y VY Pignolo Robert J RJ Duan Lishu L Liu Yijie Y Stock Stuart R SR McGuire Tammy L TL Lu Bao B Gerard Norma P NP Shore Eileen M EM Kaplan Frederick S FS Kessler John A JA

Journal of cellular biochemistry 20111001 10

Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive bone morphogenetic protein (BMP) signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP ...[more]

PMID: 21748788

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Project description:BackgroundHeterotopic ossification (HO), either acquired (aHO) or hereditary, such as fibrodysplasia ossificans progressiva (FOP), is a serious condition without effective treatment. Understanding of the core process of injury-induced HO is still severely limited.MethodsDouble-pulse thymidine analog labeling was used to explore the distinctive domains evolved in injury-induced lesions in an animal model of HO (Nse-BMP4). Histological studies were performed to see whether a similar zonal pattern is also consistently found in biopsies from patients with aHO and FOP. In vivo clonal analysis with Rainbow mice, genetic loss-of-function studies with diphtheria toxin A (DTA)-mediated depletion and lineage tracing with Zsgreen reporter mice were used to obtain further evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells. Immunohistochemistry was used to test whether vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Similar methods also were employed to further understand the signaling pathways that regulate the niche and the resultant HO.ResultsWe found that distinctive domains evolved in injury-induced lesions, including, from outside-in, a mesenchymal stem cell (MSC) niche, a transient domain and an inner differentiated core in an animal model of HO (Nse-BMP4). A similar zonal structure was found in patients with aHO and FOP. In vivo clonal analysis with Rainbow mice and genetic loss-of-function studies with DTA provided evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells; consistently, vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Further mechanistic study found that BMP and hedgehog (Hh) signaling co-regulate the niche and the resultant HO.ConclusionsAvailable data provide evidence of a potential core mechanism in which multiple disease-specific cellular and extracellular molecular elements form a unique local microenvironment, i.e., an injury-induced stem cell niche, which regulates the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). The implication for HO is that therapeutic approaches must consider several different disease specific factors as parts of a functional unit, instead of treating one factor at a time.

Project description:Traumatic heterotopic ossification (tHO) commonly develops in wounded service members who sustain high-energy and blast-related traumatic amputations. Currently, no safe and effective preventive measures have been identified for this patient population. Bone morphogenetic protein (BMP) signaling blockade has previously been shown to reduce ectopic bone formation in genetic models of HO. In this study, we demonstrate the efficacy of small-molecule inhibition with LDN193189 (ALK2/ALK3 inhibition), LDN212854 (ALK2-biased inhibition), and BMP ligand trap ALK3-Fc at inhibiting early and late osteogenic differentiation of tissue-resident mesenchymal progenitor cells (MPCs) harvested from mice subjected to burn/tenotomy, a well-characterized trauma-induced model of HO. Using an established rat tHO model of blast-related extremity trauma and methicillin-resistant Staphylococcus aureus infection, a significant decrease in ectopic bone volume was observed by micro-computed tomography imaging following treatment with LDN193189, LDN212854, and ALK3-Fc. The efficacy of LDN193189 and LDN212854 in this model was associated with weight loss (17%-19%) within the first two postoperative weeks, and in the case of LDN193189, delayed wound healing and metastatic infection was observed, while ALK3-Fc was well tolerated. At day 14 following injury, RNA-Seq and quantitative reverse transcriptase-polymerase chain reaction analysis revealed that ALK3-Fc enhanced the expression of skeletal muscle structural genes and myogenic transcriptional factors while inhibiting the expression of inflammatory genes. Tissue-resident MPCs harvested from rats treated with ALK3-Fc exhibited reduced osteogenic differentiation, proliferation, and self-renewal capacity and diminished expression of genes associated with endochondral ossification and SMAD-dependent signaling pathways. Together, these results confirm the contribution of BMP signaling in osteogenic differentiation and ectopic bone formation and that a selective ligand-trap approach such as ALK3-Fc may be an effective and tolerable prophylactic strategy for tHO.

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Substance P signaling mediates BMP-dependent heterotopic ossification.

Publications

Substance P signaling mediates BMP-dependent heterotopic ossification.

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