Attenuation of Post-Traumatic Osteoarthritis After Anterior Cruciate Ligament Injury Via Inhibition of Hedgehog Signaling.

We aimed to investigate whether post-traumatic osteoarthritis (PTOA) progression is appropriately represented by a PTOA mouse model using a unique climbing cage to add mechanical loading after anterior cruciate ligament (ACL) transection and to determine how Hedgehog signaling inhibition prevents PTOA progression by observing time-dependent morphological changes. This controlled laboratory study histologically compared mice with surgically-induced ACL transection (ACLT) and those with voluntary increased activity in a climbing cage from 1 week postoperatively (ACLT + climbing). We generated conditional knockout (cKO) mice with a deleted Smoothened (Smo) gene. Time-dependent histopathological, immunohistochemical, and gene expression analyses were performed. The ACLT + climbing group showed more severe cartilage defects and massive osteophyte formation than the ACLT group. Smo deletion significantly suppressed PTOA progression. The time-dependent assessment revealed cartilaginous processes of equivalent size at the posterior tibial margin in the Smo cKO and control mice at 4 weeks postoperatively. However, at 8 weeks postoperatively, mature ossifying lesions were detected in the controls but not in Smo cKO mice. In the articular cartilage, ADAMTS5 and RUNX2 expression were observed in hypertrophic chondrocytes near the defective cartilage in controls but not in Smo cKO mice. Climbing exercise after ACLT accelerated PTOA progression more severely not only through increasing joint instability induced by ACLT but also through mechanical loading force induced by climbing exercise. Hedgehog signaling inhibition attenuated PTOA progression by suppressing chondrocyte hypertrophy induced by mechanical loads, to which ACL-deficient athletes are usually exposed. Thus, Hedgehog signaling inhibition may be a therapeutic option to prevent arthritic changes in athletes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:609-619, 2020.

Elcatonin prevents bone loss caused by skeletal unloading by inhibiting preosteoclast fusion through the unloading-induced high expression of calcitonin receptors in bone marrow cells.

This study aimed to clarify whether elcatonin (EL) has a preventive action on bone dynamics in skeletal unloading. Seven-week-old male C57BL/6J mice with either ground control (GC) or tail suspension (TS) were administered EL 20U/kg or a vehicle (veh) three times per week and assigned to one of the following four groups: GCEL, GCveh, TSEL, and TSveh. Blood samples and bilateral femurs and tibias of the mice were obtained for analysis. After 7days of unloading, the trabecular bone mineral density in the distal femur obtained via peripheral quantitative computed tomography and the trabecular bone volume were significantly higher in the TSEL group than in the TSveh group. The bone resorption histomorphometric parameters, such as the osteoclast surface and osteoclast number, were significantly suppressed in the TSEL mice, whereas the number of preosteoclasts was significantly increased. The plasma level of tartrate-resistant acid phosphatase-5b (TRACP-5b) was significantly lower in the TSEL group than in all other groups. In the bone marrow cell culture, the number of TRACP-positive (TRACP(+)) multinucleated cells was significantly lower in the TSEL mice than in the TSveh mice, whereas the number of TRACP(+) mononucleated cells was higher in the TSEL mice. On day 4, the expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), cathepsin K and d2 isoform of vacuolar ATPase V0 domain (ATP6V0D2) mRNA in the bone marrow cells in the TSEL mice was suppressed, and the expression of calcitonin receptor (Calcr) mRNA on day 1 and Calcr antigen on day 4 were significantly higher in the TSveh mice than in the GCveh mice. EL prevented the unloading-induced bone loss associated with the high expression of Calcr in the bone marrow cells of mouse hindlimbs after tail suspension, and it suppressed osteoclast development from preosteoclasts to mature osteoclasts through bone-resorbing activity. This study of EL-treated unloaded mice provides the first in vivo evidence of a physiological role of EL in the inhibition of the differentiation process from preosteoclasts to osteoclasts.

[Analysis of tendon injuries accompanying distal radius fractures using volar locking plates].

We examined 6 cases of tendon injuries that accompanied distal radius fractures using volar locking plate between April 2006 and March 2012. Male: one case, female: five cases, average age 57.0 (33~70) years old. The fracture type was A2 in one case, A3 in four cases, and C2 in one case by AO classification. The average period for operation waiting was 2.7 days. We analyzed the time of occurrence of tendon rupture (extensor pollicis longus (EPL)ï½¥flexor pollicis longus (FPL)), the existence or not of screw prominence and dorsal roof fragment, and the positioning of the plate setting. The tendon ruptures were EPL in four cases, and FPL in two cases. The average period of rupture occurrence was 86.8 (1~182) days. In four EPL tendon ruptures we recognized one marked screw prominence (16.7%), and two dorsal roof fragments (50%), both showing widespread displacement. Moreover, we recognized the malposition of the plate setting in the two cases of FPL tendon rupture (100%). The incidence of tendon ruptures accompanying distal radius fractures using volar locking plates was not low at all, therefore we should more pay attention to the prevention of this occurrence.

Disruption of aldehyde dehydrogenase 2 gene results in altered cortical bone structure and increased cortical bone mineral density in the femoral diaphysis of mice.

INTRODUCTION: Aldehyde dehydrogenase 2 (ALDH2) degrades acetaldehyde produced by the metabolism of alcohol. The inactive ALDH2 phenotype is prevalent in East Asians, and an association between this ALDH2 polymorphism and osteoporosis has been reported. In our previous study, we found that alcohol consumption results in decreased trabecular bone volume in aldh2 knockout (aldh2(-/-)) mice compared with the volume in wild-type (aldh2(+/+)) mice. However, the effect of aldh2 gene on the skeletal phenotype in the absence of alcohol consumption remains unknown. The aim of this study was to clarify the effect of aldh2 disruption on femoral bone structure and dynamics in aldh2-disrupted mice in the absence of alcohol consumption. MATERIALS AND METHODS: We examined aldh2(-/-) and aldh2(+/+) mice at the ages of 4, 8 and 12weeks. The femoral bone length and bone mineral density (BMD) were measured using peripheral quantitative computed tomography. The mechanical strength was assessed by the three-point bending test at 12weeks, and cortical bone histomorphometry at the femur diaphysis was performed at all three time points. Osteogenic activities in aldh2(-/-) and aldh2(+/+) mice were assessed by osteoblast culture from calvariae of the neonatal mice. Bilateral femoral and tibial bones containing no bone marrow cells of 8-week-old mice were used for analysis of mRNA expression. In addition, mRNA expression in aldh2(-/-) and aldh2(+/+) mice after tail suspension or climbing exercise for 7days from 8weeks was analyzed to clarify the response to mechanical loading. RESULTS: At 12weeks, there were no significant differences in femoral bone length, trabecular BMD in the distal metaphyses of the femurs, or mechanical strength between aldh2(-/-) and aldh2(+/)(+) mice, whereas cortical BMD and cortical thickness were significantly increased and cross-sectional area and bone marrow area were significantly decreased in the femoral diaphysis of aldh2(-/-) mice relative to the corresponding values in aldh2(+/+) mice. At 8weeks, bone formation rate and mineral apposition rate on the periosteal and endocortical surfaces were significantly increased in aldh2(-/-) mice relative to the rates in aldh(+/+) mice. Calvarial osteoblast culture study revealed that the percentage of alkaline phosphatase stained cells was significantly higher in aldh2(-/-) mice compared to that in aldh(+/+) mice. Quantitative real-time RT-PCR revealed a significant increase in the expressions of bmp2, osterix, runx2, and col1a1 mRNA in aldh2(-/-) mice, along with an increase in the expression of wnt5a mRNA and the lrp5/sost mRNA ratio. The mRNA expressions of bmp2, osterix, runx2 and pthr in aldh2(-/-) mice were significantly decreased after climbing exercise compared to those in the control, although the mRNA expressions of bmp2, osterix, runx2 were not significantly decreased and pthr mRNA expression was increased in aldh(+/+) mice after climbing exercise. CONCLUSION: Our results show that disruption of aldh2 gene resulted in altered cortical bone structure and dynamics in mice. Cross-sectional area was decreased. Cortical BMD was increased owing to the promotion of cortical bone formation on the periosteal and endocortical surfaces of the femoral diaphysis. The possible mechanisms underlying altered cortical bone structure in aldh2(-/-) mice were gene-related higher osteogenic activity of osteoblasts and weakened osteogenice response to mechanical loading in growth period.

Mechanical comparison of novel bioabsorbable plates with titanium plates and small-series clinical comparisons for metacarpal fractures.

BACKGROUND: The use of bioabsorbable implants to negate the need for subsequent removal could offer major clinical advantages for the fixation of fractures. The aims of this study were to compare the mechanical properties of novel bioabsorbable plates with those of titanium plates in a fracture model and to demonstrate the clinical results of the use of these new plates for metacarpal fractures. METHODS: The first set of experiments compared the mechanical properties of bioabsorbable and titanium plates. Two types of bioabsorbable plates (one-third tubular and semi-tubular in cross-section) made of hydroxyapatite/poly-L-lactide and two types of titanium plates (for 1.5 and 2.0-mm screws) were tested. Each plate was fixed on a polyether ether ketone (PEEK) rod, which was transversely cut at its midsection. The second part of the study compared the clinical results associated with the bioabsorbable and titanium plates that were used in sixteen nonrandomized consecutive patients with metacarpal fractures. RESULTS: The bending strength and stiffness of one-third tubular bioabsorbable plate constructs were comparable with those of titanium plates for 1.5-mm screws, and those of one-half tubular bioabsorbable plates were comparable with those of titanium plates for 2.0-mm screws. The mean torsional strength (and standard deviation) of the semi-tubular bioabsorbable plates (79.0 ± 7.9 N.cm) was significantly greater than that of titanium plates for 2.0 mm screws (56.7 ± 4.0 N.cm) (p < 0.05). There were no significant differences in six-month postoperative clinical results between patients who received bioabsorbable plates and those who received titanium plates (total range of active motion, 267.0° ± 6.0° compared with 250.0° ± 28.3°; grip strength, 92.7% ± 19.7% compared with 86.4% ± 28.6% of that on the contralateral side). CONCLUSIONS: The bending strength, stiffness, and torsional strength of novel one-third or semi-tubular bioabsorbable plates, when fixed on a PEEK rod, were comparable with those for titanium plates for 1.5 or 2.0-mm screws. There were no significant differences in clinical results between these two types of plates in a small group of patients after short-term follow-up.