Disruption of the aldehyde dehydrogenase 2 gene increases the bone anabolic response to intermittent PTH treatment in an ovariectomized mouse model.

Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that oxidizes the acetaldehyde produced by alcohol metabolism. This variant not only affects the response to alcohol but is also associated with several diseases, such as esophageal cancer, myocardial infarction, and particularly osteoporosis. In our previous study, we reported that compared to wild-type (WT) mice, Aldh2 knockout (KO) mice naturally have a strong bone formation ability, and high expression of parathyroid hormone receptor (PTHR1) in osteocytes. The effect of the Aldh2 gene on bone metabolism in response to intermittent PTH treatment is unknown. The purpose of this study was to clarify the effect of the Aldh2 gene on the bone anabolic response to intermittent PTH treatment in ovariectomized mice. Female KO and WT mice were ovariectomized at 8 weeks of age. At 14 weeks of age, the KO and WT mice were divided into vehicle-treated (Veh) and PTH-treated (PTH) groups (i.e., the WT-Veh, WT-PTH, KO-Veh and KO-PTH groups). PTH (1-34) and vehicle were subcutaneously administered to each group at a dose of 40 µg/kg body weight (BW) five times per week for 4 weeks. Micro-CT showed that the bone volume (BV), trabecular number (Tb.N), connectivity density (Conn.D), and cortical thickness (Ct.Th) values in the KO-PTH mice were significantly higher than those in the KO-Veh mice. Histomorphometric analysis showed that the BV, Tb.N, and mineral apposition rate (MAR) values in the KO-PTH group were significantly higher than those in the KO-Veh group. The mRNA expression level of PTHR1 in the KO-PTH group was significantly increased and that of p21 in the KO-PTH group was significantly decreased compared with the levels in the KO-Veh group. The expression of PTHR in osteocytes from the KO-PTH group was also significantly increased compared with that in osteocytes from the KO-Veh group. Furthermore, cell cultures revealed that the ALP+CFU-f/total CFU-f percentage was significantly higher in the KO-PTH group than in the KO-Veh group. We concluded that in ovariectomized Aldh2 KO mice, the bone anabolic response to intermittent PTH treatment was significantly enhanced compared to that in WT mice, which may be mediated by the high expression level of PTHR1.

Chronic obstructive pulmonary disease severity in middle-aged and older men with osteoporosis associates with decreased bone formation.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a risk factor for osteoporosis. Nevertheless, much remains unclear regarding the bone metabolism dynamics associated with COPD. The present study focuses on the associations between the COPD severity and serum bone metabolism biomarkers. METHODS: We enrolled 40 patients who visited the orthopedics departments at our institutions and underwent dual-energy X-ray absorptiometry between September 2015 and December 2017. Only male osteoporosis patients over 45 years of age were included, and 5 patients were excluded due to disease or use of internal medicines affecting bone metabolism. All subjects underwent lung function testing, spine radiography, and blood tests. We measured percent forced expiratory volume in 1 second (%FEV1), which reflects COPD severity, and we examined the relationships between %FEV1 and serum levels of bone metabolism biomarkers. RESULTS: All subjects were diagnosed with osteoporosis based on T-scores. %FEV1 correlated with body weight, body mass index (BMI), and Z-score/T-scores. %FEV1 moderately correlated with serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b in the partial correlation analysis adjusted for BMI or T-score in the lumbar vertebrae. We performed a hierarchical multiple regression analysis to identify that serum ALP and P1NP were the independent explanatory variables to %FEV1 independent of other factors. CONCLUSIONS: The data suggest that the COPD severity in middle-aged and older men with osteoporosis associates with decreased bone formation. COPD patients may exhibit bone metabolism dynamics characterized by low bone turnover with osteogenesis dysfunction as COPD becomes severe.

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.

[An Experience of Using a Distraction Plate for an Elderly Patient with a Highly Communited Intraarticular Distal Radius Fracture].

We performed open reduction and internal fixation using a distraction plate in two cases of elderly patients with highly communited intraarticular open distal radius fractures. There was no corrective loss of intraarticular fracture fragment in either case. The implant was removed in one case because bone union was achieved. The plate was retained in the other case, without the hope of implant removal. Neither case complained of any marked disturbance of activities of daily living (ADL), and there was no pain at the time of the final follow up period. However, there is a high possibility of limitation of the range of motion (ROM) of the wrist after implant removal, therefore we need to judge the indications carefully.

Systemic bone loss, impaired osteogenic activity and type I muscle fiber atrophy in mice with elastase-induced pulmonary emphysema: Establishment of a COPD-related osteoporosis mouse model.

Although it is suggested that chronic obstructive pulmonary disease (COPD) and bone are related, almost all of the pathological mechanisms of COPD-related osteoporosis remain unknown. There is a mouse model showing a deterioration of bone quality after cigarette smoke exposure; however, in smoking exposure models, various factors exist that affect bone metabolism, such as smoking and body weight loss (muscle and fat mass loss). We considered it appropriate to use an elastase-induced emphysema model to exclude factors influencing bone metabolism and to investigate the influence of pulmonary emphysema on bone metabolism. The purpose of this study was to establish a COPD/emphysema-related osteoporosis mouse model by using the elastase-induced emphysema model. The lumbar vertebrae and femurs/tibiae exhibited trabecular bone loss and impaired osteogenic activity in 24-week-old male elastase-induced emphysema model mice. In addition, the model mice showed atrophy of type I muscle fibers without atrophy of type II muscle fibers. We believe that the mice described in this experimental protocol will be accepted as a COPD/emphysema-related osteoporosis mouse model and contribute to further investigations.

Cortical bone loss due to skeletal unloading in aldehyde dehydrogenase 2 gene knockout mice is associated with decreased PTH receptor expression in osteocytes.

Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that degrades and detoxifies the acetaldehyde produced by alcohol metabolism. In our previous study, we found that compared with wild-type mice (WT), climbing exercises did not increase trabecular bone mass in Aldh2 knockout mice (KO). The purpose of this study was to clarify the effect of the Aldh2 gene on cortical bone structure and on the dynamics of skeletal unloading. Eight-week-old male KO and WT were divided into ground control (GC) or tail suspension (TS) groups for one week (i.e., the KOGC, KOTS, WTGC and WTTS groups). We measured the bone mineral density (BMD) of the femur using dual-energy X-ray absorptiometry. We assessed the femoral morphometry using peripheral quantitative computed tomography (pQCT) and evaluated the femoral cortex histomorphometry, and cortical mRNA using quantitative RT-PCR and cortical bone immunohistostaining. No significant differences were found between the femoral BMD of WTGC and that of WTTS, but the BMD in KOTS was significantly lower than that of KOGC. The pQCT results revealed that the cortical BMD of the femoral diaphysis in KOTS was significantly lower than that of KOGC. Furthermore, the cortical bone area and cortical thickness were significantly lower in KOTS than in the other three groups. Cortical histomorphometric analysis revealed that the endosteal and periosteal bone formation parameters were significantly lower in KOTS than in KOGC. Bone formation signals such as parathyroid hormone receptor (PTHR) were significantly decreased in KOTS compared with the levels in KOGC. Cortical bone immunohistostaining revealed a significantly decreased expression of PTHR in the osteocytes of KOTS compared with the expression level in KOGC. Thus, we concluded that when the Aldh2 gene is disrupted, skeletal unloading suppresses bone formation to decrease cortical bone mass, which may be mediated by a decreased expression of PTH receptors in osteocytes.

Disruption of the Aldehyde Dehydrogenase 2 Gene Results in No Increase in Trabecular Bone Mass Due to Skeletal Loading in Association with Impaired Cell Cycle Regulation Through p21 Expression in the Bone Marrow Cells of Mice.

Approximately 45% of people of East Asian descent have the inactive aldehyde dehydrogenase 2 (ALDH2) phenotype. The enzyme defect of ALDH2 has been found to adversely influence the risk of osteoporosis. The aim of this study was to clarify the effect of skeletal loading on trabecular bone structure and dynamics in Aldh2-disrupted mice in the absence of alcohol consumption. Four-week-old male Aldh2-/- (KO) and Aldh2+/+ (WT) mice were divided into a ground control (GC) group and a climbing exercise (CE) group in each genotype. The trabecular bone mineral density of the distal femur measured by peripheral quantitative computed tomography in the wild-type CE (WTCE) group was significantly higher than that in the wild-type GC (WTGC) group; however, there was no significant difference between the knockout CE (KOCE) and knockout GC (KOGC) groups. Bone histomorphometry revealed that osteogenic parameters were significantly increased in the WTCE group compared with the WTGC group, but not increased in the KOCE group compared with the KOGC group. Quantitative reverse transcriptase polymerase chain reaction and flow cytometry revealed that mRNA and protein expression levels of p21 were significantly decreased in the WTCE group compared with those in the WTGC group, while these differences were not observed between the KOGC and KOCE groups. This study provides the first in vivo evidence that p21 expression in the bone marrow is not decreased after skeletal loading and osteoblast differentiation is impaired in the absence of Aldh2 gene.