Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment

Abstract

Osteoporosis is characterized by increased bone turnover, low bone mass and an increased risk of fracture. The bone loss results from an imbalance between bone resorption and formation. Osteoporosis continues to be a major health problem. Approximately 200 million adults worldwide have osteoporosis [1,2], and approximately 30% of all postmenopausal women in the Europe and the USA have osteoporosis [3]. Notwithstanding the availability of effective treatments for osteoporosis, such as the bisphosphonates (alendronate, risedronate, ibandronate and zoledronate), estrogen-based therapies, selective estrogen receptor modulators (raloxifene and bazedoxifene), parathyroid hormone and other niche treatments, including vitamin D derivatives and strontium (in some countries), many individuals with osteoporosis remain untreated. Although many individuals with osteoporosis remain undiagnosed, this lack of treatment may also reflect poor tolerability and mechanism-based toxicities of current therapies for osteoporosis. New therapies for osteoporosis that may potentially improve or augment existing therapies include the recently approved anti-Receptor Activator of NF-KappaB-ligand monoclonal antibody (denosumab/Prolia) and the cathepsin K (CatK) inhibitor odanacatib (ODN), presently in late stage clinical development. Cells involved in bone remodeling:osteoblasts and bone formation Bone is a dynamic tissue that undergoes continual adaption during life to attain and preserve skeletal size, shape and structural integrity and regulate mineral homeostasis. Two processes, remodeling and modeling, underpin development and maintenance of the skeletal system. Bone modeling is responsible for growth and mechanically induced adaption of bone and requires that the process of bone formation and bone resorption, while globally coordinated, occur independently at distinct anatomical location. This tightly coordinated event requires the synchronized activities of multiple cellular participants to ensure bone resorption and formation occur sequentially at the same anatomical location to preserve bone mass. Bone remodeling is a physiological process that maintains the integrity of the skeleton by removing old bone and replacing it with a young matrix. Two principle cell types are found in bone, the osteoclast, and the osteoblast, which are the major effectors in the turnover of bone matrix (Fig. 1) [4,5]. Osteoblasts and osteoclasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Osteoblasts are specialized mesenchymal-derived cells C e l l u l a r a n d m o l e c u l a r m e c h a n i s m s o f o s t e o p o r o s i s : c u r r e n t c o n c e p t s a n d f u t u r e d i r e c t i o n t r e a t m e n t The article presents review of literature dedicated to the contemporary view on the cellular-molecular mechanisms of the bone remodeling and pathogenesis of the osteoporosis. The discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in process bone remod...

Effect of Golimumab on Immunological Markers for Bone Metabolism and on Arterial Stiffness in Patients With Rheumatoid Arthritis

“…Таким образом, проведенные исследования выявили изменения в системе трансмембранных молекул RANKL/ОПГ у больных РА, что может быть связано с активностью паннуса, клетки которого обладают способностью к агрессивному росту и являются продуцентами целого ряда провоспалительных медиаторов, прежде всего ФНОα, интерлейкина 1β (ИЛ1β), ИЛ6, факторов роста, потенцирующих гиперэкспрессию RANKL [14]. В свою очередь ОПГ, продуцируемый остеобластами, является естественным антагонистом RANKL, препятствующим его взаимодействию с RANK, в результате чего разрушение костей остеокластами тормозится [5]. Поэтому выявленное в нашем исследовании преимущественное увеличение в сыворотке крови содержания ОПГ на ранних стадиях РА можно рассматривать как компенсаторный механизм, направленный на нивелирование активности RANKL.…”

“…В то же время у больных с длительным анамнезом заболевания выявлено преобладание гиперпродукции RANKL, что вызывает сдвиг соотношения RANKL/ОПГ в сторону RANKL и указывает на прогрессирование процессов костной деструкции. Полагают также, что высокий уровень RANKL приводит к повышению соотношения RANKL/ОПГ, направляя гладкомышечные клетки сосудов по пути остеобластической дифференциации [5].…”

“…Работы последних лет свидетельствуют о том, что у пациентов с ОП имеет место более высокий кардиоваскулярный риск (КВР), чем у лиц со здоровой костной тканью, и дают основание предполагать наличие корреляции между ОП и атеросклерозом [3,4] как параллельно протекающими деструктивными процессами в двух тканях с развитием фатальных и нефатальных кардиоваскулярных событий [5] и повышением риска переломов костей. В пользу данной гипотезы свидетельствует обнаружение в артериальной стенке ряда белков -регуляторов процессов костеобразования и костной резорбции.…”

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