Novel mouse model of spinal cord injury-induced heterotopic ossification

Abstract

Abstract-Heterotopic ossification (HO) develops in about 20% to 30% of patients with spinal cord injury (SCI) and significantly impairs their rehabilitation. There is no effective prevention or treatment for this condition at this time. Our current understanding of its etiology and pathophysiology is limited partially due to the lack of clinically relevant animal models. In this study, we report a novel mouse model of SCI-induced HO by administering a subthreshold dose of bone morphogenetic protein (BMP)-2 to muscles in mice after SCI. Microcomputed tomography scanning showed that an intramuscular injection of 0.25 micrograms of BMP-2 causes significant HO in mice with SCI but not in control (sham surgery) mice. Our analysis of gene expression showed significantly increased BMP signaling in quadriceps following SCI, suggesting that BMP signaling may play a role in SCI-induced HO. Administering 0.25 micrograms of BMP-2 to the front arms of the mice with SCI also results in the development of significant HO but not in control mice. This suggests that SCI causes a systematic osteogenic effect, which is not limited to paralyzed limbs. This novel mouse model will serve as a powerful tool in exploring the molecular mechanisms of SCI-induced HO, which may lead to novel treatment for this disease.

Crosstalk between substance P and calcitonin gene‐related peptide during heterotopic ossification in murine Achilles tendon

“…We also investigated the effects of these neuropeptides on BMP2 expression. Other groups have shown delivery of exogenous BMP2 induces HO in various animal models of HO . In this study, BMP2 staining was positive in all treatment groups.…”

“…Other groups have shown delivery of exogenous BMP2 induces HO in various animal models of HO. 14,35,58 In this study, BMP2 staining was positive in all treatment groups. SP-treated tendons showed localized expression around the heterotopic bones and chondrocytes, leading to an overall higher expression of BMP2 in these tendons.…”

“…1,5,6,10 To better understand HO pathophysiology, we developed an animal model that used local delivery of neuropeptides SP and CGRP to a targeted tendon site and reliably induced HO at that site. This approach has significant advantages over existing HO models that use genetic modification, administration of exogenous BMP or induce trauma to the tissue, 12,14,34,35,58 which lack precise control over modulation of specific signaling molecules at HO sites, and potentially confound the data interpretation. Using our novel model, we discovered a potential crosstalk between SP and CGRP, where SP promoted HO alone, and CGRP counteracted SP effects in HO induction in tendon.…”

Peripheral denervation participates in heterotopic ossification in a spinal cord injury model

“…Regarding molecular signals involved in our model, we failed to demonstrate increased expression of BMP signaling pathway in muscles after SCI as described by Kang et al [ 51 ]. However experimental designs were focused on different time points, respectively eighteen hours after SCI in our protocol versus 3 days in Kang’s study.…”

Bone morphogenetic protein signaling in rotator cuff muscle atrophy and fatty infiltration

“…Thus, most previous work on muscle BMP signaling focuses on heterotopic ossification (abnormal bone development in soft tissue). In our previous work in trauma 14 and spinal cord injury 15 induced heterotopic ossifications, we found that BMP-2, 4, 7 and 9 are upregulated in muscle during heterotopic ossification. BMP signaling in muscle atrophy and fatty infiltration is poorly understood.…”