SNX10在石骨症中的分子机制研究进展

石骨症也称阿耳伯斯?尚堡氏病（Albers Schonberg disease）、大理石骨病（Marble bone disease）等,是一种以骨吸收障碍导致的广泛骨密度增加为标志的罕见疾病,主要与破骨细胞（OCL）功能障碍有关。最近的研究证实了石骨症具有高度的遗传异质性,涉及多种基因突变（TCIRG1、CLCN7、SNX10、OSTM1、PLEKHM1、CAII、RANKL、RANK）。然而,仍有超过25%的患者发病于未知类型的基因突变。分选连接蛋白10型（SNX10）是一种新发现的石骨症相关因子。为含PX结构域的分选连接蛋白亚型,参与破骨重吸收过程中质子泵（V-ATPase）的囊泡运输,从而导致重吸收过程的H+分泌障碍,即严重的OCL丰富型常染色体隐性石骨症（ARO）。本文主要从SNX10的功能、SNX10已知的突变类型、临床病例及治疗等方面,针对SNX10与石骨症关系进行系统的阐述。     

家族性石骨症骨折1例

患者，女，20岁，2003年12月15日因行走时不慎摔倒致左股部外伤伴疼痛、活动受限入院。经X线检查诊断为：①左股骨转子下病理性骨折；②右髂骨翼骨折；③石骨症。于当日在硬膜外麻醉下行手术治疗。术中发现骨折处血肿不明显，骨折断端整齐，断缘平直锐利，髓腔完全封闭，骨质坚硬。用联合钻钻孔时发现骨碎屑如同粉笔末，骨质坚硬，钻孔十分困难，放弃动力髋内固定，改用钢板螺丝钉固定。术后化验检查患者血清钙、血清磷正常，肝、肾功能正常，血甲状旁腺素和降钙素均正常。     

Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing.

As dominant regulators of osteoclastogenesis and bone resorption, receptor activator of NFkappaB (RANK), receptor activator of NFkappaB ligand, and OPG have been identified as ideal drug targets for the treatment of metabolic bone disease. One concern regarding the therapeutic use of RANK signaling inhibitors is their effect on fracture healing. Therefore we tested if uncoupling and osteoclast depletion via RANK blockade affects callus formation, maturation and matrix remodeling, as well as union rates in a mouse tibia fracture model. Low dose (1 mg/kg i.p.) RANK:Fc therapy had no effect on callus formation, matrix maturation and remodeling, and resulted in 100% bony union by day 28. High dose RANK:Fc treatment (10 mg/kg i.p.) effectively eliminated osteoclasts at the fracture site on day 14, with no significant effects on fracture healing. When therapy was discontinued, normal numbers of osteoclasts were observed at the fracture site by day 28. However, continuous therapy resulted in a large osteopetrotic callus consisting of both mineralized and unmineralized matrix that was void of osteoclasts, but bony union was unaffected at day 28. We also evaluated this process in the complete absence of RANK signaling using RANK -/- mice. These animals exhibited significant radiographic and histologic evidence of callus formation, indicating that RANK signaling is not required for fracture callus formation. However, only 33% of RANK -/- animals formed bony unions compared to 100% of the osteopetrotic control mice. This defect was most likely a result of decreased blood flow, as evidenced by fewer blood vessels in the RANK -/- animals. Together, these data imply that osteoclast depletion via inhibition of RANK signaling is a viable option for the treatment of pathological bone loss since no adverse effects on fracture healing are observed when therapy is discontinued.     

Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis

Autosomal recessive osteopetrosis is a severe hereditary bone disease whose cellular basis is in the osteoclast, but with heterogeneous molecular defects. We hereby report the clinical and the molecular study of seven patients affected by the recessive form of osteopetrosis (ARO) from six families originating from the Middle-East: four from Lebanon and two from Syria. Parental consanguinity was found in five families. The mean age of diagnosis was 3 months. Failure to thrive, prominent forehead, exophthalmia, optic atrophy, hepatosplenomegaly, neurological manifestations, anaemia, thrombocytopenia, hypocalcaemia, elevated hepatic enzymes and acid phosphatase, and an early fatal outcome were common. Macrocephaly, strabismus, and brain malformations were relatively less common. Mutations were identified in two genes: TCIRG1 and OSTM1. Phenotype-genotype correlation is discussed.     

石骨症的临床及X线表现——着重分析7个家族22例

目的探讨家族性石骨症的遗传、临床及X线表现特点.方法对59例石骨症患者临床资料作回顾性总结分析.结果在家族性病例中以恶性型(幼儿型)居多,多在Ⅰ、Ⅱ代发病,偶见连续三代发病者.散发型中则以良性型(成人型)为主.X线表现以骨质硬化,髓腔闭塞为基本特征,椎体"夹心征"及髂骨"同心圆征"为其特征性表现.结论临床工作中要注重对石骨症患者进行家系调查,尤其对有遗传倾向者,有必要在胎儿期进行检测.     

Rheumatoid arthritis associated with osteopetrosis

Abstract

Osteopetrosis is an inherited disorder characterized by reduced bone resorption. We here report a rare case of osteopetrosis associated with rheumatoid arthritis. The patient was diagnosed as autosomal dominant osteopetrosis type II in his youth and developed rheumatoid arthritis at 42 years of age. In spite of the severe inflammation and rapid progression of cartilage destruction, the progression of bone erosion was slow in this patient.     

“Challenges in the management of fractures in osteopetrosis”! Review of literature and technical tips learned from long-term management of seven patients

Osteopetrosis is a metabolic disorder with diminished bone resorption due to osteoclastic abnormality. It causes hard and brittle marble bone which fractures easily. Most of these fractures can be treated conservatively. Operative intervention when needed presents with unique technical challenges. While osteopetrotic hard bone may be penetrated with a drill bit; high friction and prolonged drilling can make the drill bit blunt. The heat generated can cause bone necrosis and break the drill bit. Besides this, brittleness of bones can cause intra-operative fractures. Due to the difficulties during the operation, the operative time may be prolonged thereby increasing the risk of post-operative infection. There is also a risk of delay in consolidation and non-union owning to impaired bone remodelling.We present an account of seven patients treated for various fracture related problems occurring throughout their life due to this disease. Difficulties encountered during their treatment prompted us to present some general management principles.     

Phenotypic Characteristics of Bone in Carbonic Anhydrase II-Deficient Mice

Carbonic anhydrase II (CAII)-deficient mice were created to study the syndrome of CAII deficiency in humans including osteopetrosis, renal tubular acidosis, and cerebral calcification. Although CAII mice have renal tubular acidosis, studies that analyzed only cortical bones found no changes characteristic of osteopetrosis. Consistent with previous studies, the tibiae of CAII-deficient mice were significantly smaller than those of wild-type (WT) mice (28.7 ± 0.9 vs. 43.6 ± 3.7 mg; p < 0.005), and the normalized cortical bone volume of CAII-deficient mice (79.3 ± 2.2%) was within 5% of that of WT mice (82.7 ± 2.3%; p < 0.05), however, metaphyseal widening of the tibial plateau was noted in CAII-deficient mice, consistent with osteopetrosis. In contrast to cortical bone, trabecular bone volume demonstrated a nearly 50% increase in CAII-deficient mice (22.9 ± 3.5% in CAII, compared to 15.3 ± 1.6% in WT; p < 0.001). In addition, histomorphometry demonstrated that bone formation rate was decreased by 68% in cortical bone (4.77 ± 1.65 μm³/μm²/day in WT vs. 2.07 ± 1.71 μm³/μm²/day in CAII mice; p < 0.05) and 55% in trabecular bone (0.617 ± 0.230 μm³/μm²/day in WT vs. 0.272 ± 0.114 μm³/μm²/day in CAII mice; p < 0.05) in CAII-deficient mice. The number of osteoclasts was significantly increased (67%) in CAII-deficient mice, while osteoblast number was not different from that in WT mice. The metaphyseal widening and changes in the trabecular bone are consistent with osteopetrosis, making the CAII-deficient mouse a valuable model of human disease.     

Brain Abscess in a Patient with Osteopetrosis: A Rare Complication

Brain abscess formation is extremely rare in patients with osteopetrosis. Herein, we report a case of viridans streptococci brain abscess in an immunocompromised child diagnosed with osteopetrosis. The patient presented with a sudden change in mental status and convulsions. Radiological evaluation revealed a temporal lobe brain abscess, and intravenous antibiotherapy was started immediately. The patient underwent abscess drainage, and laboratory investigation of pus material revealed viridans streptococci.