Bone Remodeling: Cellular Aspects - Literature review Example

Bone Remodeling: Cellular aspects There is a considerable increase in research in bone biology during the last to decades and thus have lead in increasing our approach and understanding towards the bone remodeling. Bone is a dynamic tissue that constantly undergoes remodeling even after the growth and modeling the whole skeleton is complete. It is process in which localized removal of bone which is replaced by the newly formed bone takes place. Osteoclast and Osteoblast are the two principle types of cell types found in bone.(11) They are the major effectors in the turnover matrix. They contribute to skeletal mass, structure and strength, by osteoclasts helps in resorbing the bone whereas the osteoblast in forming the bone. Bone remodeling is a process of a lifetime in which the old bone is removed by the osteoclasts and replaced by osteoblasts.(9) Parafitt AM., 2002 described the cellular basis of the normal bone remodeling sequence in the human adult to a cycle that constitutes three stages, quiescence, activation, resorption, reversal, formation, and return to quiescence (1). The major reasons of remodeling is to enable the bones to respond and adapt to mechanical stress as occurs as a result of physical exercise and during the mechanical lading as occurs during orthodontic tooth movement. This article outlines the major research carried out in the past decade in the cellular basis of bone remodeling. The aspects included are the relationship between the hormone and localized factors that affect the phenomenon. The dependence of the localized factors and the proteins during the bone resorption is critically discussed. The understanding provided by the RANK/RANKL/OPG paradigm for both the differentiation and their activation of the osteoclast is also discussed. Recent research works Bone undergoes constant bone remodeling and it is a very complex process. In his review article Hill PA., 1998 described four stages involved in bone remodeling, namely, resorptive phase reversal phase, formative phase and resting phase. In the resorptive phase, the activated multinucleated osteoclast derived from bone marrow resorbs a discrete area of mineralized bone matrix. The latter stage than follows in which the osteoblast precursor cells, which can locally proliferate and differentiate into osteoblast migrate into the resorption lacuna and disclose the former osteoclastic activity. The osteoblast deposits new bone matrix which is initially unmineralized and called osteroid and in this way fills the resorption lacuna. This phase is the formative phase. Finally the resting phase is followed. Once embedded in the osteroid, the osteoblast matures into terminally differentiated osteocytes. The osteoblast lying on the surface on the surface of the newly formed bone packet are quiescent lining cells activated.(11) Osteoclast and osteoblast lay the basis of bone remodeling and significant research is been carried out in the past decade. It is known that both osteoblasts and osteoclasts function under the regulation of many factors(3, 7), systemic and local among which insulin, insulin-like growth factors-I, bone-morphogenetic factors and Wnt protins are the potent bone anabolic factors(13). Recently, it was reported that phosphoinosidine-dependent serine-threonine protein kinase Akt plays a major role in signaling of the potent bone anabolic factors. Akt1, a major Akt in osteoclast and osteoblast has a novel role. Akt1 phosphorylates the transcription factor FoxO3a to restrict its nuclear localization, thus suspending the transactivation of its target gene Bim which is also known to be a potent proapoptotic molecule in osteoblasts. This research established that Akt1 plays a crucial regulator of osteoclast and osteoblast by promoting the differentiation and survival to maintain bone marrow and turnover.(8) Bone resporption is mainly dependent on a cytokine RANKL (receptor activator of nuclear factor kappa B ligand), which is a TNF (tumor necrosis factor), that is vital for the osteoclast formation, activity and survival in normal and pathologic states of bone remodeling. OPG (osteoprotegerin), a TNF receptor family that binds to RANKL and thus preventing the activation of its single cognate receptor called RANK. Studies indicate that a relative balance in RANKL and OPG is required for the activity of osteoclast. The RANKL receptors are also known to prevent bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis.(9) The bone resorption pathway included number of steps directed towards the removal of both the mineral and organic constituents of bone matrix by the osteoclasts, assisted by the osteoblast.(12) Osteoclasts ultimately go through apoptosis which is characterized by the nuclear and cytoplasmic condensation and fragmentation of nuclear DNA into nucleosized units. TGF- that is responsible for bone resorption is reported for programmed cell death in osteoclasts, while the osteoclast stimulatory factors, PTH (parathyroid hormone) and 1,25-dihyroxyvitamin D3, inhibit osteoclast apoptosis in vitro.(6) The results suggesting that the regulation of the life span plays a significant role in the normal bone remodeling process, that either increases of stops the osteoclastic bone resorption.(11) In his earlier studies Baldoct et al., 2006 reported that in the envelope specific bone remodeling activity in transgenic mice model over expressed the vitamin D receptor (VDR) specifically in the mature cells of the osteoblastic lineage (OSVDR).(2) The pleiotropic effects of vitamin D on bone cells were found to be consistent on both sided of the bone remodeling response in the OSVDR mice., but the effects were always location specific, the bone formation and the mineral apposition increased solely on the periosteal surfaces and the resorption decreased, specially in the cancellous compartment.(5) This finding laid the basis for exploring the role of vitamin D action and regulation of Bone Remodelling. The results indicated that the vitamin D mediated osteoclastogenesis reduced in OSVDR mice, which was restricted to chow and calcium-restricted diets, with the effects concentrating to cacellous bone. The vitamin-D mediated reduction in OPG expression OSVDR osteoblast was decreased in OSVDR osteoblast in vivo and in vitro, thus resulting in a decreased RANKL/OPG ratio in OSVDR compared to the wild-type after the exposure to vitamin D. This led to the conclusion by the researchers that mature osteoblast play hindering role in bone resorption with active vitamin D metabolites acting through the VDR to increase OPG. The inhibition was less active in the cacellous bone, thus effectively targeting this region for resorption after the systemic release of the activated vitamin D metabolites.(2) Osteoprotegrin (OPG) and soluble receptor activator of NF-Kappa B ligand (sRANKL) together regulate the bone metabolism among other cytokines, whereas cathepsin K is known a potent collagen-degrading activity. It is postulated that an imbalance of this system is partly responsible for the skeletal complications of RA. This postulation laid to the recent research carries out by Skoumal et al., 2007. The relationship between OPG, sRANKL and cathepsin K of hundred patients with active and longstanding RA. It was detected that the serum levels of cathepsin k and OPG was increased. But normal levels were found in sRANKL levels. There was no correlation with the over expressed OPG and sRANKL. The researchers speculated that the increased levels of OPG is effective in compensating the action of sRANKL, but does not directly prevent bone degradation, as shown by the data serum levels of cathepsin K.(12) Recently, there is been discussions and reports on the mechanism that regulate the osteoclastic differentiation, but very less is known of the process or means through which the resorptive activity is controlled, especially in relating to human osteoclasts. Fuller et al., 2007 recently developed an essay that allows measuring the resorptive activity by minimizing the confounding effects on differentiation by optimizating osteoclastogenesis, so that measurable resorption occurs over a short period, and by relating resorption in each culture during the test period to the resorption that had occurred in the same culture in a prior control period. The researchers found that RANKL strongly stimulated the release of CTX-I by osteoclast over a similar range to that over which it induces osteoclastic differentiation consistent with a distinct action on osteoclastic function. Further, factors like PTH, TNF-alpha, IL-6, IL-8, VEGFm IL-1, MCP-2, IFN had no significant effect. In addition to that, the resorption was also strongly suppressed by aledronate, the protease inhibitor E64, and cathepsin inhibitor MV061194. The release of MMP-driven collagen fragment ICTP represented less than 0.01% of the quantity of CTX-I release in the culture samples. The study concluded that MMPs make a very small contribution to the bone-resorptive activity in osteoclasts.(4) In vitro studies have shown that osteoclast in both mice and humans may form directly form the precursor cell populations of monocytes and macrophages. It sis suggested that MCP-1 may lay role in hormone-stimulated bone remodeling through the action of osteoclast. But, the relationship between the MCP and PTH (para-thyroid hormone) has never been investigated. Recently, Li et al., 2007 proposed a model that suggested that expression of MCP-1 is involved in osteoclast recruitment and differentiation at the stage of fusion and multinulceation of osteoclast precursors. This hypothesis lay the basis for increased osteoclastic activity in the anabolic effect of PTH, apart from RANKL stimulation, to initiate greater bone remodeling in a transient time-dependent fashion. The results suggested that upon PTH treatment the pKA pathway is activated in osteoblast, resulting in the expression of RANKL on the membrane and secretion of MCP-1. Osteoclast and precursor monocytes are recruited to the remodeling site by MCP-1 to initiate the process of bone remodeling. Simultaneously, MCP-1 facilitates the fusion of the pre-osteoclast forming mature osteoclasts through a paracrine mode.(10) Summary and conclusion: Bone remodeling is a complex process that involves a number of cellular functions that are directed towards the coordinated resorption and that finally leads to the formation of a new bone. This process if very strictly regulated by localized factors and hormones. The latter regulates the synthesis, activation, and effects of the local factors that have direct action on cellular and differentiated function of cells of the osteoclast and differentiated function of cells of the osteoclast and osteoblast. It is postulated that the role of hormones is to provide tissue specificity for a given growth factor, because most of these factors are synthesizes by a variety of skeletal and non skeletal muscles.(2, 3, 6, 10, 11). There is so rapid increase in the knowledge of the multiple regulatory mechanisms within the bone should aid the understanding of physiological bone remodeling and also favor potential explanation for the changes in bone turnover seen in the various disease states. This information will pave a new path for devising new therapeutics to control the formation of the bone and the resorption based upon the novel regulatory mechanisms. While our knowledge of the cellular events underlying osteoclast formation and activation had flourished in the past years, there needs to be more studies to clarify the interactions of the multiple signal transduction pathways. The future should discover new molecules that will lead to further insight into the homeostatic mechanism responsible for bone formation and resorption. Reference: 1. AM, P. 2002. Targeted and Nontargeted Bone Remodeling: Relationship to Basic Multicellular Unit Origination and Progression. Bone 30:5-7. 2. Baldock PA, T. G., Hodge JM,Baker SUK, Dressel U, O'Loughlin PD,Nicholson GC,Briffa KH, Eisman JA, Gardiner EM. 2006. Vitamin D Action and Regulation of Bone Remodeling: Suppression of Osteoclastogenesis by the Mature Osteoblast. Journal ob Bone and Mineral Research 21:1618-1626. 3. Boyle WJ, S. W., Lacey DL. 2003. Osteoclast differentiation and activation. Nature:337-342. 4. Fuller K, K. B., Chambers TJ. 2007. Regulation and enzymatic basis of bone resorption by human osteoclasts. Clin Sci (Lond). 112:567-75. 5. Gardiner EM, B. P., Thomas GP, Sims NA, Henderson NK, Hollis B, White CP, Sunn KL, Morrison NA, Walsh WR, Eisman JA. 2000. Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage. FASEB J 14:1908-1916. 6. GD, R. 1996. Advances in bone biology:the osteoblast. Endocrinology reviews 17:308-332. 7. Harada S, R. G. 2003. Control of osteoblast function and regulation of bone mass. Nature 423:349-355. 8. Kawamura N, K. F., Oshima Y,Ohba S,Ikeda T, Saito T,Shinoda Y,Kawasaki Y,Ogata N, Hoshi K,Akiyama T,Chen WS, Hay N,Tobe K,Kadowaki T,Azuma Y,Tanaka S,Nakamura K,Chung U,Kawaguchi H. 2007. Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling. PLoS ONE 24:1058. 9. Kearns AE, K. S., Kostenuik P. 2007. RANKL and OPG Regulation of Bone Remodeling in Health and Disease. Endocrinolgy Review. 10. Li X, Q. L., Bergenstock M,Bevelock LM, Novack DV,Partridge NC. 2007. Parathyroid Hormone Stimulates Osteoblastic Expression of MCP-1 to Recruit and Increase the Fusion of Pre/Osteoclasts. The Journal of Biological Chemistry 282:33098-33106. 11. PA, H. 1998. Bone Remodelling. British Journal of Orthodontics 25:101-107. 12. Skoumal M, H. G., Kolarz G, Hawa G, Woloszczuk W, Klingler A,Varga F, Klaushofer K. 2007. The imbalance between osteoprotegerin and cathepsin K in the serum of patients with longstanding rheumatoid arthritis. Rheumatology Journal. 13. Thrailkill KM, L. C. J., Bunn RC, Kemp SF, Fowlkes JL. 2005. Is insulin an anabolic agent in bone Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab. 289:E735-745. Read More