Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression.

Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

Post-traumatic distal ulnar bifurcation in children: a case report.

BACKGROUND: Galeazzi fracture dislocation is a compound injury that encompasses fractures of the distal third of the radius and dislocation of the distal radial ulnar joint (DRUJ). Clinically, this condition is rare and often leads to distal ulnar bifurcation. In previous similar reports, patients were effectively managed through surgery. CASE PRESENTATION: In this case report, we describe an 11-year-old male child who presented with an ulnar bifida following trauma to the hand, and was treated with manipulation and conservative treatment without surgery. A follow-up performed over the years demonstrated that the patient recovered well, and had normal wrist movements without significant pain, and the patient expressed great satisfaction. CONCLUSIONS: Ulnar diaphyseal fracture may occur in children or adolescents due to injuries, and may be accompanied with manipulation and repositioning. Conservative treatment can be applied to avoid the trauma associated with surgery especially in the absence of severe joint mobility impairment with good outcomes.

Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature.

BACKGROUND: Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY: A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION: We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

MiR-19b-3p regulates osteogenic differentiation of PDGFRα+ muscle cells by specifically targeting PTEN.

Heterotopic ossification (HO) is a common disturbing complication of intra-articular fractures. Its prevention and treatment are still difficult as its pathogenesis is unclear. It was reported that PDGFRα+ muscle cells in skeletal muscle may participate in the formation of HO; however, the specific mechanism is still unknown. This study investigated the function of miR-19b-3p in osteogenic differentiation of PDGFRα+ muscle cells. MiR-19b-3p was upregulated during PDGFRα+ muscle cell osteogenic differentiation. The exogenous expression of miR-19b-3p led to an increase in osteogenic marker gene transcription and translation during the osteogenic differentiation of PDGFRα+ muscle cells. Furthermore, both alkaline phosphatase and alizarin red staining increased in miR-19b-3p mimic transfected cells. Over-expression of miR-19b-3p led to the down-regulation of gene of phosphate and tension homology deleted on chromosome ten (PTEN). Additionally, the dual luciferase reporter assay demonstrated that PTEN was a direct target of miR-19b-3p. The increase of osteocalcin, osteopontin, and Runt-related transcription factor 2 protein levels induced by ectopic miR-19b-3p expression could be partially reversed by PTEN over-expression. In conclusion, our results suggested that miR-19b-3p may be a promising target in inhibiting PDGFRα+ muscle cell osteogenic differentiation and treatment of HO.

Effects of the acetabular fracture index and other factors of posterior wall acetabular fracture on functional outcome.

Objective To analyze the effects of the acetabular fracture index (AFI) and other factors on the functional outcome of patients with acetabular fractures involving the posterior wall. Methods Forty-eight patients who underwent surgery in our department were reviewed. According to the AFI, which indicates the percentage of remaining intact posterior acetabular arc, the patients were divided into Group A (AFI ≤ 25%, 11 patients), Group B (25% < AFI ≤ 50%, 23 patients), Group C (50% < AFI ≤ 75%, 7 patients), and Group D (75% < AFI ≤ 100%, 7 patients). The AFI was measured with a computed tomography picture archiving and communication system or calculated with the cosine theorem. A nonparametric test and ordinal regression were used to determine the role of the AFI and other factors on the functional outcome. Perioperative information, including demographic and fracture-related data, reduction quality, physical therapy duration, association with a lower limb fracture and avascular necrosis of the femoral head were prospectively gathered. Results The mean AFIs of A, B, C, and D groups were 14.3%, 35.9%, 59.5%, and 81.2%, respectively. No statistically significant differences were observed among the groups for demographic and fracture-related data. A better reduction quality (OR = 4.21, 95%CI 1.42 ∼ 12.43, χ2 = 6.781, P = 0.009) and a larger value of AFI (OR = 2.56, 95%CI 1.18 ∼ 5.55, χ2 = 5.648, P = 0.017) result in a higher functional score. The functional outcome of a physical therapy duration of more than 12 months (OR = 0.15, 95%CI 0.02 ∼ 0.90, χ2 = 4.324, P = 0.038) was better than that of less than 12 months. Lower limb fracture (OR = 0.13, 95%CI 0.02 ∼ 0.74, χ2 = 5.235, P = 0.022) and avascular necrosis of femoral head (OR = 0.02, 95%CI 0.00 ∼ 0.87, χ2 = 4.127, P = 0.042) were found to correlate with a lower functional score. Conclusion With a greater of AFI, the functional outcome score would be better. Other factors, including reduction quality, physical therapy duration, association with a lower limb fracture, and avascular necrosis of the femoral head, most likely also affect hip functional recovery.

GDF8 inhibits bone formation and promotes bone resorption in mice.

Growth Differentiation Factor 8 (GDF8), also called myostatin, is a member of the transforming growth factor (TGF)-ß super-family. As a negative regulator of skeletal muscle growth, GDF8 is also associated with bone metabolism. However, the function of GDF8 in bone metabolism is not fully understood. Our study aimed to investigate the role of GDF8 in bone metabolism, both in vitro and in vivo. Our results showed that GDF8 had a negative regulatory effect on primary mouse osteoblasts, and promoted receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro. Intraperitoneal injection of recombinant GDF8 repressed bone formation and accelerated bone resorption in mice. Furthermore, treatment of aged mice with a GDF8 neutralizing antibody stimulated new bone formation and prevented bone resorption. Thus, our study showed that GDF8 plays a significant regulatory role in bone formation and bone resorption, thus providing a potential therapeutic pathway for osteoporosis.

Increased serum GDF11 concentration is associated with a high prevalence of osteoporosis in elderly native Chinese women.

Osteoporosis is an age-related disease. Many studies have confirmed the anti-aging effect of growth differentiation factor 11 (GDF11), but the action of GDF11 on bone metabolism remains unclear. In this study, we aimed to investigate the relationship between serum GDF11 levels and the prevalence of osteoporosis. Our data indicate negative correlations between serum GDF11 levels and BMD at the lumbar spine and femoral neck. The serum GDF11 levels were grouped into quartile intervals, and the prevalence and risk of osteoporosis were found be markedly greater with increased GDF11 levels. This study demonstrated that GDF11 was negatively correlated with BMD in elderly Chinese women. Furthermore, osteoporotic risk was significantly increased with increases in GDF11 levels.

[ZEPHIR plate fixation in anterior surgery of the cervical spondylotic myelopathy].

OBJECTIVE: To evaluate the clinical outcome of ZEPHIR plate in treating cervical spondylotic myelopathy(CSM). METHODS: We retrospectively analyzed 18 patients undergoing anterior decompression fusion and internal fixation with ZEPHIR plate. Follow-up period ranged from 3 to 12 months (an average of 9 months). The bone graft fusion rate, rehabilitation of neurological deficits, and the complications of the hardware were observed. We assessed the clinical effect with JOA score. RESULTS: Rehabilitation of neurological deficits were observed in 16 patients, The JOA score after the operation significantly increased than before the operation. The fusion rate was 100%, the intervertebral height were maintained, and no complications related to the plate were found. CONCLUSION: ZEPHIR plate in the treatment of cervical spondylotic myelopathy may increase the fusion rate of the bone graft significantly with low incidence of complication.