This study aimed to investigate the effect of repetitive tensile loading on the expression of BMP-2 and the effect of BMP-2 on the osteogenic differentiation of tendon-derived stem cells (TDSCs) in vitro. Repetitive stretching was applied to TDSCs isolated from rat patellar tendon at 0%, 4%, and 8%, 0.5 Hz. The expression of BMP-2 was detected by Western blotting and qPCR. To study the osteogenic effects of BMP-2 on TDSCs, BMP-2 was added to the TDSC monolayer for the detection of ALP activity and calcium nodule formation in a separate experiment. TDSCs adhered, proliferated, and aligned along the direction of externally applied tensile force while they were randomly oriented in the control group. Western blotting showed increased expression of BMP-2 in 4% and 8% stretching groups but not in the control group. Up-regulation of BMP-2 mRNA was also observed in the 4% stretching group. BMP-2 increased the osteogenic differentiation of TDSCs as indicated by higher ALP cytochemical staining, ALP activity, and calcium nodule formation. Repetitive tensile loading increased the expression of BMP-2 and addition of BMP-2 enhanced osteogenic differentiation of TDSCs. Activation of BMP-2 expression in TDSCs during tendon overuse might provide a possible explanation of ectopic calcification in calcifying tendinopathy. Keywords: tendon-derived stem cells; calcifying tendinopathy; osteogenic differentiation; BMP-2; mechanical stimulation Calcifying tendinopathy is a tendon disorder with calcium deposits in the mid-substance presented with symptoms including chronic activity-related pain. It is a special case of tendinopathy and the presence of calcified deposits in calcifying tendinopathy worsens its clinical manifestations. Its underlying pathogenesis is poorly understood and treatment is usually symptomatic. Understanding the pathogenesis of calcifying tendinopathy is essential for its effective evidence-based management.Chondrocytes phenotype/markers were expressed in clinical samples of tendinopathy and calcifying tendinopathy.1,2 We reported the presence of chondrocyte phenotype and ectopic ossification in a calcifying tendinopathy model 3 and the expression of bone morphogenetic protein-2 (BMP-2) protein at those sites, 4 suggesting that BMP-2 might be involved in the pathogenesis. This was further supported by the ectopic overexpression of BMPs in the subacromial bursa of patients with chronic degeneration of rotator cuff. 5Tendons harbored stem cells (tendon-derived stem cells, TDSCs) that could differentiate into chondrocytes and osteoblasts. 6 As we observed earlier expression of BMP-2 mRNA and protein at week 2 in healing tendon cells, before the time of its appearance in chondrocyte-like cells and calcified deposits in our
Background: Ectopic chondrogenesis and ossification were observed in a degenerative collagenase-induced calcific tendinopathy model and to a lesser extent, in a patellar tendon traumatic injury model. We hypothesized that expression of bone morphogenetic protein-2 (BMP-2) contributed to ectopic chondrogenesis and ossification. This study aimed to study the spatial and temporal expression of BMP-2 in our animal models.
Chondrocytes phenotype/markers were expressed in clinical samples of tendinopathy and calcifying tendinopathy. This study examined the spatial-temporal expression of chondro-osteogenic Bone Morphogenetic Proteins (BMPs), which might contribute to ectopic chondro-osteogenesis and failed healing process in tendinopathy. Collagenase was injected into patellar tendon of rats to induce ossified failed tendon healing. At week 2, 4, 8, 12, and 16, the patella tendon was harvested for immunohistochemical staining and analysis of BMP-2/ 4/7. BMP-4/7 showed similar expression patterns, which was different from BMP-2. The expression of BMP-2 in the tendon matrix increased at week 2 and was reduced to nearly undetectable level afterwards except at the chondro-ossification sites. However, the expression of BMP-4/7 in the healing tendon fibroblast-like cells and matrix increased at week 2, reduced at week 4 and 8 and increased again at week 12 and 16, consistent with transient healing at week 8 in this animal model. There was increasing strong expression of BMP-4/7 in the chondrocyte-like cells in the un-ossified and ossified areas from week 8-16. BMP-4/7, besides BMP-2, might also contribute to ectopic chondro-osteogenesis and failed healing in tendon injuries. BMP-4/7, but not BMP-2, might be involved in regulating late events in ossified failed tendon healing. Keywords: tendinopathy; failed tendon healing; BMP-2/4/7; ectopic chondrogenesis; ectopic ossificationChronic tendinopathy refers to a broad spectrum of pathological conditions in tendons and their insertion, with symptoms including activity-related chronic pain, which is prevalent among athletes and sedentary subjects. Despite its prevalence, its underlying pathogenesis is poorly understood and treatment is usually symptomatic. Failed healing was suggested as the pathological mechanism of tendinopathy. 1 Chondrocyte phenotype/ markers were expressed in clinical samples of tendinopathy and calcifying tendinopathy. 2,3 We reported the presence of chondrocyte phenotype and ectopic ossification in our collagenase-induced failed tendon healing model. 4 We have shown this collagenase animal model to reproduce many key histopathological features of clinical tendinopathy and can be used to study the ossified failed healing process in tendinopathy. 5 We further reported the expression of bone morphogenetic protein-2 (BMP-2) protein, an osteogenic growth factor, around the chondrogenic and ossifying sites in the same animal model, 6 suggesting that BMP-2 might be involved in the pathogenesis. This was further supported by ectopic over-expression of BMPs in the subacromial bursa of patients with chronic degeneration of the rotator cuff. 7 Our result also showed that repetitive cyclic loading could increase the expression of BMP-2 in tendonderived stem cells (TDSCs) and that BMP-2 could induce the osteogenic differentiation of TDSCs in vitro. 8 To date, more than 20 BMPs have been identified and many of them were chondro-osteogenic. We hypothesized that other chondro-...
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