Expression of calcitonin gene-related peptide induces ligament degeneration through endochondral ossification in osteoarthritis.

AIM: Osteoarthritis (OA) is a disease in which degeneration occurs in various tissues such as cartilage and subchondral bone. Degeneration of ligaments also plays an important role in OA progression, resulting in an increase in chondrocytes and ossification, but the factor that causes this is still unclear. It is reported that the expression of calcitonin gene-related peptide (CGRP) increases OA progression, and CGRP might play a role in ligament degeneration because CGRP has a function in endochondral ossification. The purpose of this study is to analyze the mechanism of ligament degeneration and the function of CGRP. METHODS: To examine the relationship between ligament degeneration and CGRP expression, human posterior cruciate ligaments (PCL) from OA patients, and senescence-accelerated mouse prone 8 (SAMP8) mice were histologically analyzed. The effect of CGRP on human ligament cells on chondrogenesis, osteogenesis, and adipogenesis was also examined. RESULTS: In human PCL and SAMP8 mice, CGRP expression increased as degeneration progressed, and decreased in severe degeneration. CGRP was expressed in the chondrocyte-like cells with SOX9. CGRP-positive cells expressing type II collagen increased with OA progression. CGRP upregulated the gene expression of VEGF, SOX9, RUNX2, COL10a1, and MMP13 in the human ligament cells. CGRP also promoted chondrogenesis and osteogenesis from the human ligament cells. CONCLUSION: During OA progression, CGRP plays a role in the transdifferentiation from ligament cells to chondrocytes and promotes endochondral ossification in the ligament. CGRP would be the therapeutic target to prevent ligament degeneration.

The role of substance P on maintaining ligament homeostasis by inhibiting endochondral ossification during osteoarthritis progression.

PURPOSE: Osteoarthritis (OA) is characterized by the degeneration of various tissues, including ligaments. However, pathological changes such as chondrogenesis and ossification in ligaments during OA are still unclear. Substance P (SP), a neuropeptide, has various functions including bone metabolism. This study aimed to analyze the expression and function of SP in OA ligaments, and the therapeutic potential of SP agonists in OA mice. MATERIALS AND METHODS: Expressions of SP, SOX9, and MMP13 were histologically analyzed in the posterior cruciate ligament (PCL) in humans with OA and Senescence-accelerated mouse-prone 8 (SAMP8) mice as a spontaneous OA model. The effect of SP agonists on chondrogenesis was evaluated using human ligament cells. Finally, SP agonists were administered intraperitoneally to destabilized medial meniscus (DMM) mice, and the PCL was histologically evaluated. RESULTS: In PCL of humans and mice, the expression of SP, SOX9, and MMP13 was upregulated as OA progressed, but their expression was downregulated in severe degeneration. SP and SOX9 were co-expressed in chondrocyte-like cells. In ligament cells, SP agonists downregulated SOX9, RUNX2, and COL10A1. On evaluating chondrogenesis in ligament cells, pellet diameter was reduced in those treated with the SP agonists compared to those untreated. Administration of SP agonists ameliorated PCL degeneration in DMM mice. The Osteoarthritis Research Society and ligament scores in mice with SP agonists were significantly lower than those without SP agonists. CONCLUSIONS: SP plays an important role in maintaining ligament homeostasis by inhibiting endochondral ossification during OA progression. Targeting SP has therapeutic potential for preventing ligament degeneration.

Monitoring Vascular Compromise Using Ultrasound After Free Tissue Transfer.

OBJECTIVES: To report the clinical utility of high-resolution ultrasound (US) for monitoring vascular compromise after free tissue transfer. METHODS: Fifty-two tissue transfers in the extremities were included in this study. Blood flow around the anastomotic pedicle and subcutaneous tissue of the grafted flap was monitored with pulsed color and power Doppler US whenever the conventional monitoring method, comprising the bedside assessment of the temperature, capillary refill, and flap color, showed abnormalities until 1 week after reconstruction. RESULTS: All flaps were indicated for US monitoring, with 44 flaps showing Doppler signals in each position, even though conventional flap monitoring showed an abnormality. Forty of the 44 flaps showed no flap failure, whereas the remaining 4 flaps developed partial necrosis. Abnormal US findings were noted in 8 of the 52 flaps. Ultrasound revealed interruption of venous blood flow around the anastomotic pedicle in 6 of 8 flaps. Emergent exploration revealed venous occlusion at the anastomotic pedicle, similar to the US finding. In 2 of the 8 flaps, US showed no blood flow to either the anastomotic pedicle or subcutaneous tissue. Emergent exploration revealed arterial occlusion at the anastomotic pedicle. Seven of the 8 reexplored flaps were salvaged after revision surgery with complete flap survival. Partial flap survival was noted in 1 case, but complete flap failure was avoided. CONCLUSIONS: Ultrasound is a useful adjunct that enables a direct assessment of perfusion in grafted tissues, which may reduce unnecessary exploration when conventional flap monitoring shows an abnormality.