Vascular calcification or ectopic mineralization in blood vessels is an active, cell-regulated process, increasingly recognized as a general cardiovascular risk factor. Ectopic artery mineralization is frequently accompanied by decreased bone mineral density or disturbed bone turnover and development of the osteoporosis. The latest data support the correlation of osteoporosis and atherosclerosis, indicating the parallel progression of two tissue destruction processes with increased fatal and nonfatal coronary events, as well as a higher fracture risk. Patients with osteoporosis, have a higher risk of cardiovascular diseases than subjects with normal bone. Many proteins responsible for bone formation and resorption have been identified in the arterial wall. Vascular calcification includes mostly osteogenic and, to a lesser extent chondrogenic differentiation of osteoblasts and osteoclast-like cells. It has been shown that many of the regulators of bone formation and resorption some bone structural proteins, such as osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) are also expressed in the atherosclerotic plaque. When RANKL binds to RANK, osteoclasts are activated and bone resorption occurs and processes of vascular calcification become also activated. OPG, protein homologue to receptor activator of nuclear factor-κB (RANK), can bind to RANKL, blocking the binding of RANKL to RANK, that results in inhibition of differentiation of preosteoclasts to mature osteoclasts, lower osteoclast capacity for resorption of bone mineral matrix, and development vascular calcification. The latest data supports that cathepsin K, a cysteine protease, can efficiently degrade type I and II collagen, both of which are major matrix components of the bone and atherosclerotic plaque. These findings further underscore the potential of cathepsin K as a target for novel molecules to treat osteoporosis and atherosclerosis. Thus, the discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in the process of bone remodeling, vascular calcification and atherosclerosis has made progress in understanding the mechanisms of disease development and possibly to develop new dual therapies. New therapies for osteoporosis and atherosclerosis that may potentially improve or augment existing treatments include the recently approved anti-receptor activator of NF-κB-ligand monoclonal antibody fms (denosumab) and the cathepsin K inhibitor odanacatib, presently in the late stage of clinical development.
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...
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