Perlecan,a heparan sulfate proteoglycan,acts as a mechanical sensor for bone to detect external loading.Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome(SJS)and atten...Perlecan,a heparan sulfate proteoglycan,acts as a mechanical sensor for bone to detect external loading.Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome(SJS)and attenuates loading4nduced bone formation in perlecan deficient mice(Hypo).Considering that intracellular calcium[Ca2+]i is an ubiquitous messenger controlling numerous cellular processes including mechanotransduction,we hypothesized that perlecan deficiency impairs bone’s calcium signaling in response to loading.To test this,we performed real-time[Ca2+]i imaging on in situ osteocytes of adult murine tibiae under cyclic loading(8 N,Figure 1).Relative to wild type(WT),Hypo osteocytes showed decreases in the overall[Ca2+]i response rate(-58%),calcium peaks(-33%),cells with multiple peaks(-53%),peak magnitude(-6.8%),and recovery speed to baseline(-23%).RNA sequencing and pathway analysis of tibiae from mice subjected to one or seven days of unilateral loading demonstrated that perlecan deficiency significantly suppressed the calcium signaling,ECM-receptor interaction,and focal adhesion pathways following repetitive loading.Defects in the endoplasmic reticulum(ER)calcium cycling regulators such as Ryr1/ryanodine receptors and Atp2a1/Sercal calcium pumps were identified in Hypo bones.Taken together,impaired calcium signaling may contribute to bone’s reduced anabolic response to loading,underlying the osteoporosis risk for the SJS patients.展开更多
骨肉瘤(osteosarcoma,OS)是最常见的原发性骨恶性肿瘤,具有很高的局部浸润和转移倾向。c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNK)是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族中极为重要的一员,而且JNK信...骨肉瘤(osteosarcoma,OS)是最常见的原发性骨恶性肿瘤,具有很高的局部浸润和转移倾向。c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNK)是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族中极为重要的一员,而且JNK信号通路已被证明参与调控了OS的发生发展。该文就JNK信号通路调控OS的增殖、迁移、侵袭、血管生成、自噬、凋亡和焦亡等生物学行为,以及氧化应激和非编码RNA通过JNK信号通路对OS调控的研究进展进行综述,进一步探究JNK信号通路的内在调控机制,为寻找OS的治疗提供新的思路。展开更多
基金supported by NIH grants ( P30GM103333,R01AR054385)supported partially by a core access award through NIH NIGMS IDeA Program grant ( P20GM103446)
文摘Perlecan,a heparan sulfate proteoglycan,acts as a mechanical sensor for bone to detect external loading.Deficiency of perlecan increases the risk of osteoporosis in patients with Schwartz-Jampel Syndrome(SJS)and attenuates loading4nduced bone formation in perlecan deficient mice(Hypo).Considering that intracellular calcium[Ca2+]i is an ubiquitous messenger controlling numerous cellular processes including mechanotransduction,we hypothesized that perlecan deficiency impairs bone’s calcium signaling in response to loading.To test this,we performed real-time[Ca2+]i imaging on in situ osteocytes of adult murine tibiae under cyclic loading(8 N,Figure 1).Relative to wild type(WT),Hypo osteocytes showed decreases in the overall[Ca2+]i response rate(-58%),calcium peaks(-33%),cells with multiple peaks(-53%),peak magnitude(-6.8%),and recovery speed to baseline(-23%).RNA sequencing and pathway analysis of tibiae from mice subjected to one or seven days of unilateral loading demonstrated that perlecan deficiency significantly suppressed the calcium signaling,ECM-receptor interaction,and focal adhesion pathways following repetitive loading.Defects in the endoplasmic reticulum(ER)calcium cycling regulators such as Ryr1/ryanodine receptors and Atp2a1/Sercal calcium pumps were identified in Hypo bones.Taken together,impaired calcium signaling may contribute to bone’s reduced anabolic response to loading,underlying the osteoporosis risk for the SJS patients.
文摘骨肉瘤(osteosarcoma,OS)是最常见的原发性骨恶性肿瘤,具有很高的局部浸润和转移倾向。c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNK)是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族中极为重要的一员,而且JNK信号通路已被证明参与调控了OS的发生发展。该文就JNK信号通路调控OS的增殖、迁移、侵袭、血管生成、自噬、凋亡和焦亡等生物学行为,以及氧化应激和非编码RNA通过JNK信号通路对OS调控的研究进展进行综述,进一步探究JNK信号通路的内在调控机制,为寻找OS的治疗提供新的思路。
