By using surgical mouse models, this study investigated how the tissue environment influences the osteogenic potential of muscle progenitors (m-progenitors) and potentially contributes to heterotopic ossification (HO). Injury was induced by clamping the gluteus maximus and medius (group M) or osteotomy of greater trochanter (group O) on the right hip, as well as combined muscle injury and osteotomy of greater trochanter (group M+O). The gluteus maximus and medius of the operated hips were harvested at days 1, 3, 5, and 10 for isolation of m-progenitors. The cells were cultured in an osteogenic medium for 3 weeks, and osteogenesis was evaluated by matrix mineralization and the expression of osteogenesisrelated genes. The expression of type I collagen, RUNX2 (runt-related transcription factor 2), and osteocalcin by the m-progenitors of group M+O was significantly increased, compared with groups M and O. Osteogenic m-progenitors in group O increased the expression of bone morphogenetic protein 2 and also bone morphogenetic protein antagonist differential screening-selected gene aberrative in neuroblastoma. On histology, there was calcium deposition mostly in the muscles of group M+O harvested at day 10. CD56, representing myogenic progenitors, was highly expressed in the m-progenitors isolated from group M (day 10), but m-progenitors of group M+O (day 10) exhibited the highest expression of platelet-derived growth factor receptor a (PDGFR-a), a marker of muscle-derived mesenchymal stem cells (M-MSCs). The expressions of PDGFR-a and RUNX2 were colocalized in osteogenic m-progenitors. The data indicate that the tissue environment simulated in the M+O model is a favorable condition for HO formation. Most likely, M-MSCs, rather than myogenic progenitors, in the m-progenitors participate in HO formation. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:745-753 SIGNIFICANCEThe prevalence of traumatic heterotopic ossification (HO) is high in war injury. The pathogenesis of HO is still unknown. This study clarified the contribution of a tissue environment created by bone or muscle injury to the formation of HO. The study also found that muscle-derived mesenchymal stem cells, but not myogenic progenitors, are involved in the formation of HO. The findings of this study could be used to strategize the prevention and treatment of HO.
Level IV, retrospective case series.
The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at −80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs.
Background:Posttraumatic osteoarthritis (PTOA) is secondary to an array of joint injuries. Animal models are useful tools for addressing the uniqueness of PTOA progression in each type of joint injury and developing strategies for PTOA prevention and treatment.Hypothesis:Intra-articular fracture induces PTOA pathology.Study Design:Descriptive laboratory study.Methods:Through a parapatellar incision, the medial tibial plateau was exposed in the left knees of 8 Sprague-Dawley rats. Osteotomy at the midpoint between the tibial crest and the outermost portion of the medial tibial plateau, including the covering articular cartilage, was performed using a surgical blade. The fractured medial tibial plateau was fixed with 2 needles transversely. The fractured knees were not immobilized. Before and after surgery, rat gait was recorded. Rats were sacrificed at week 8, and their knees were harvested for histology.Results:After intra-articular fracture, the affected limbs altered gait from baseline (week 0). In the first 2 weeks, the gait of the operated limbs featured a reduced paw print intensity and stride length but increased maximal contact and stance time. Reduction of maximal and mean print area and duty cycle (the percentage of stance phase in a step) was present from week 1 to week 5. Only print length was reduced in weeks 7 and 8. At week 8, histology of the operated knees demonstrated osteoarthritic pathology. The severity of the PTOA pathology did not correlate with the changes of print length at week 8.Conclusion:Intra-articular fracture of the medial tibial plateau effectively induced PTOA in rat knees. During PTOA development, the injured limbs demonstrated characteristic gait.Clinical Relevance:Intra-articular fracture represents severe joint injury and associates with a high rate of PTOA. This animal model, with histologic and gait validations, can be useful for future studies of PTOA prevention and early diagnosis.
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