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Posts Tagged ‘osteoclasts’


Reporter: Aviral Vatsa PhD, MBBS

Osteocytes are the professional mechanosensors of bone. They modulate bone remodelling in accordance with external mechanical loads by orchestrating the activity of one forming osteoblasts and bone resorbing osteoclasts. Osteocytes are at the heart of bone metabolism. They constitute >95% of bone cells. They are terminally differentiated cells and reside in the hard mineralised matrix of bone, thus making it difficult to study them in situ. However, recent developments in imaging and tissue processing have made it possible to study osteocytes in their natural milieu. Moreover, increasing number of studies have highlighted the fact that a multifaceted approach from various domains of science such as biomechanics, cell biology, bioengineering, biophysics, biomaterials, computational modelling, endocrinology, and orthopaedics is essential to further our understanding of the intricate processes involved in bone remodelling and the central role of osteocytes in maintaining bone mass and architecture.

In this post a variety of reviews from an upcoming special issue on osteocytes in the journal Bone are highlighted that help us add few more pieces of knowledge to the ever growing eclaircissements on the subject.

1. Measurement and estimation of osteocyte mechanical strain

Review Article
Amber Rath Stern, Daniel P. Nicolella

Abstract

Osteocytes are the most abundant cell type in bone and are responsible for sensing mechanical strain and signaling bone (re)modeling, making them the primary mechanosensors within the bone. Under aging and osteoporotic conditions, bone is known to be less responsive to loading (exercise), but it is unclear why. Perhaps, the levels of mechanical strain required to initiate these biological events are not perceived by the osteocytes embedded within the bone tissue. In this review we examine the methods used to measure and estimate the strains experienced by osteocytes in vivo as well as the results of related published experiments. Although the physiological levels of strain experienced by osteocytes in vivo are still under investigation, through computational modeling and laboratory experiments, it has been shown that there is significant amplification of average bone strain at the level of the osteocyte lacunae. It has also been proposed that the material properties of the perilacunar region surrounding the osteocyte can have significant effects of the strain perceived by the embedded osteocyte. These facts have profound implications for studies involving osteoporotic bone where the material properties are known to become stiffer.

2. Glucocorticoids and Osteocyte Autophagy

Review Article
Wei Yao, Weiwei Dai, Jean X. Jiang, Nancy E. Lane

Abstract

Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk is high. While previous studies have found GC effects on both osteoclasts and oteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis. This paper will review the data to support the role of GCs in osteocyte autophagy.

3. Osteocytes remove and replace perilacunar mineral during reproductive cycles

Review Article
John J. Wysolmerski

Abstract

Lactation is associated with an increased demand for calcium and is accompanied by a remarkable cycle of bone loss and recovery that helps to supply calcium and phosphorus for milk production. Bone loss is the result of increased bone resorption that is due, in part, to increased levels of PTHrP and decreased levels of estrogen. However, the regulation of bone turnover during this time is not fully understood. In the 1960s and 1970s many observations were made to suggest that osteocytes could resorb bone and increase the size of their lacunae. This concept became known as osteocytic osteolysis and studies suggested that it occurred in response to parathyroid hormone and/or an increased systemic demand for calcium. However, this concept fell out of favor in the late 1970s when it was established that osteoclasts were the principal bone-resorbing cells. Given that lactation is associated with increased PTHrP levels and negative calcium balance, we recently examined whether osteocytes contribute to bone loss during this time. Our findings suggest that osteocytes can remodel their perilacunar and pericanalicular matrix and that they participate in the liberation of skeletal calcium stores during reproductive cycles. These findings raise new questions about the role of osteocytes in coordinating bone and mineral metabolism during lactation as well as the recovery of bone mass after weaning. It is also interesting to consider whether osteocyte lacunar and canalicular remodeling contribute more broadly to the maintenance of skeletal and mineral homeostasis.

4. Studying osteocytes within their environment

Review Article
Duncan J. Webster, Philipp Schneider, Sarah L. Dallas, Ralph Müller

Abstract

It is widely hypothesized that osteocytes are the mechano-sensors residing in the bone’s mineralized matrix which control load induced bone adaptation. Owing to their inaccessibility it has proved challenging to generate quantitative in vivo experimental data which supports this hypothesis. Recent advances in in situ imaging, both in non-living and living specimens, have provided new insights into the role of osteocytes in the skeleton. Combined with the retrieval of biochemical information from mechanically stimulated osteocytes using in vivo models, quantitative experimental data is now becoming available which is leading to a more accurate understanding of osteocyte function. With this in mind, here we review i) state of the art ex vivo imaging modalities which are able to precisely capture osteocyte structure in 3D, ii) live cell imaging techniques which are able to track structural morphology and cellular differentiation in both space and time, and iii) in vivo models which when combined with the latest biochemical assays and microfluidic imaging techniques can provide further insight on the biological function of osteocytes.

5. Osteocyte apoptosis

Review Article
Robert L. Jilka, Brendon Noble, Robert S. Weinstein

Abstract

Apoptotic death of osteocytes was recognized over 15 years ago, but its significance for bone homeostasis has remained elusive. A new paradigm has emerged that invokes osteocyte apoptosis as a critical event in the recruitment of osteoclasts to a specific site in response to skeletal unloading, fatigue damage, estrogen deficiency and perhaps in other states where bone must be removed. This is accomplished by yet to be defined signals emanating from dying osteocytes, which stimulate neighboring viable osteocytes to produce osteoclastogenic cytokines. The osteocyte apoptosis caused by chronic glucocorticoid administration does not increase osteoclasts; however, it does negatively impact maintenance of bone hydration, vascularity, and strength.

6. Emerging role of primary cilia as mechanosensors in osteocytes

Review Article
An M. Nguyen, Christopher R. Jacobs

Abstract

The primary cilium is a solitary, immotile microtubule-based extension present on nearly every mammalian cell. This organelle has established mechanosensory roles in several contexts including kidney, liver, and the embryonic node. Mechanical load deflects the cilium, triggering biochemical responses. Defects in cilium function have been associated with numerous human diseases. Recent research has implicated the primary cilium as a mechanosensor in bone. In this review, we discuss the cilium, the growing evidence for its mechanosensory role in bone, and areas of future study.

7. Mechanosensation and transduction in osteocytes

Review Article
Jenneke Klein-Nulend, Astrid D. Bakker, Rommel G. Bacabac, Aviral Vatsa, Sheldon Weinbaum

Abstract

The human skeleton is a miracle of engineering, combining both toughness and light weight. It does so because bones possess cellular mechanisms wherein external mechanical loads are sensed. These mechanical loads are transformed into biological signals, which ultimately direct bone formation and/or bone resorption. Osteocytes, since they are ubiquitous in the mineralized matrix, are the cells that sense mechanical loads and transduce the mechanical signals into a chemical response. The osteocytes then release signaling molecules, which orchestrate the recruitment and activity of osteoblasts or osteoclasts, resulting in the adaptation of bone mass and structure. In this review, we highlight current insights in bone adaptation to external mechanical loading, with an emphasis on how a mechanical load placed on whole bones is translated and amplified into a mechanical signal that is subsequently sensed by the osteocytes.

8. The osteocyte in CKD: New concepts regarding the role of FGF23 in mineral metabolism and systemic complications

Review Article
Katherine Wesseling-Perry, Harald Jüppner

Abstract

The identification of elevated circulating levels of the osteocytic protein fibroblast growth factor 23 (FGF23) in patients with chronic kidney disease (CKD), along with recent data linking these values to the pathogenesis of secondary hyperparathyroidism and to systemic complications, has changed the approach to the pathophysiology and treatment of disordered bone and mineral metabolism in renal failure. It now appears that osteocyte biology is altered very early in the course of CKD and these changes have implications for bone biology, as well as for progressive cardiovascular and renal disease. Since circulating FGF23 values are influenced by therapies used to treat secondary hyperparathyroidism, the effects of different therapeutic paradigms on FGF23 have important implications for mineral metabolism as well as for morbidity and mortality. Further studies are critically needed to identify the initial trigger for abnormalities of skeletal mineralization and turnover as well as the potential effects that current therapeutic options may have on osteocyte biology.

9. Vitamin D signaling in osteocytes: Effects on bone and mineral homeostasis

Review Article
Liesbet Lieben, Geert Carmeliet

Abstract

The active form of vitamin D [1,25(OH)2D] is an important regulator of calcium and bone homeostasis, as evidenced by the consequences of 1,25(OH)2D inactivity in man and mice, which include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism and bone abnormalities. The recent generation of tissue-specific (intestine, osteoblast/osteocyte, chondrocyte) vitamin D receptor (Vdr) null mice has provided mechanistic insight in the cell-specific actions of 1,25(OH)2D and their contribution to the integrative physiology of VDR signaling that controls bone and mineral metabolism. These studies have demonstrated that even with normal dietary calcium intake, 1,25(OH)2D is crucial to maintain normal calcium and bone homeostasis and accomplishes this through this primarily through stimulation of intestinal calcium transport. When, moreover, insufficient calcium is acquired from the diet (severe dietary calcium restriction, lack of intestinal VDR activity), 1,25(OH)2D levels will increase and will directly act on osteoblasts and osteocytes to enhance bone resorption and to suppress bone matrix mineralization. Although this system is essential to maintain normal calcium levels in blood during a negative calcium balance, the consequences for bone are disastrous and generate an increased fracture risk. These findings evidently demonstrate that preservation of serum calcium levels has priority over skeletal integrity. Since vitamin D supplementation is an essential part of anti-osteoporotic therapy, mechanistic insight in vitamin D actions is required to define the optimal therapeutic regimen, taking into account the amount of dietary calcium supply, in order to maximize the targeted outcome and to avoid side-effects. We will review the current understanding concerning the functions of osteoblastic/osteocytic VDR signaling which not only include the regulation of bone metabolism, but also comprise the control of calcium and phosphate homeostasis via fibroblast growth factor (FGF) 23 secretion and the maintenance of the hematopoeitic stem cell (HSC) niche, with special focus on the experimental data obtained from systemic and osteoblast/osteocyte-specific Vdr null mice.

10. In vitro and in vivo approaches to study osteocyte biology

Review Article
Ivo Kalajzic, Brya G. Matthews, Elena Torreggiani, Marie A. Harris, Paola Divieti Pajevic, Stephen E. Harris

Abstract

Osteocytes, the most abundant cell population of the bone lineage, have been a major focus in the bone research field in recent years. This population of cells that resides within mineralized matrix is now thought to be the mechanosensory cell in bone and plays major roles in the regulation of bone formation and resorption. Studies of osteocytes had been impaired by their location, resulting in numerous attempts to isolate primary osteocytes and to generate cell lines representative of the osteocytic phenotype. Progress has been achieved in recent years by utilizing in vivo genetic technology and generation of osteocyte directed transgenic and gene deficiency mouse models.

We will provide an overview of the current in vitro and in vivo models utilized to study osteocyte biology. We discuss generation of osteocyte-like cell lines and isolation of primary osteocytes and summarize studies that have utilized these cellular models to understand the functional role of osteocytes. Approaches that attempt to selectively identify and isolate osteocytes using fluorescent protein reporters driven by regulatory elements of genes that are highly expressed in osteocytes will be discussed.

In addition, recent in vivo studies utilizing overexpression or conditional deletion of various genes using dentin matrix protein (Dmp1) directed Cre recombinase are outlined. In conclusion, evaluation of the benefits and deficiencies of currently used cell lines/genetic models in understanding osteocyte biology underlines the current progress in this field. The future efforts will be directed towards developing novel in vitro and in vivo models that would additionally facilitate in understanding the multiple roles of osteocytes.

11. Gap junction and hemichannel functions in osteocytes

Review Article
Alayna E. Loiselle, Jean X. Jiang, Henry J. Donahue

Abstract

Cell-to-cell and cell-to-matrix communication in bone cells mediated by gap junctions and hemichannels, respectively, maintains bone homeostasis. Gap junctional communication between cells permits the passage of small molecules including calcium and cyclic AMP. This cell-to-cell communication occurs between bone cells including osteoblasts, osteoclasts and osteocytes, and is important in both bone formation and bone resorption. Connexin (Cx) 43 is the predominant gap junction protein in bone cells, and facilitates the communication of cellular signals either through docking of gap junctions between two cells, or through the formation of un-paired hemichannels. Systemic deletion of Cx43 results in perinatal lethality, so conditional deletion models are necessary to study the postnatal role of gap junctions in bone. These models provide the opportunity to determine the role of gap junctions in specific bone cells, notably the osteocyte. In this review, we summarize the key roles that gap junctions and hemichannels in osteocytes play in bone cell response to many stimuli including mechanical loading, intracellular and extracellular stimuli, such as parathyroid hormone, PGE2, plasma calcium levels and pH, as well as in maintaining osteocyte survival.

12. Effects of PTH on osteocyte function

Review Article
Teresita Bellido, Vaibhav Saini, Paola Divieti Pajevic

Abstract

Osteocytes are ideally positioned to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. However, evidence supporting the involvement of osteocytes in specific aspects of skeletal biology has been limited mainly due to the lack of suitable experimental approaches. Few crucial advances in the field in the past several years have markedly increased our understanding of the function of osteocytes. The development of osteocytic cell lines initiated a plethora of in vitro studies that have provided insights into the unique biology of osteocytes and continue to generate novel hypotheses. Genetic approaches using promoter fragments that direct gene expression to osteocytes allowed the generation of mice with gain or loss of function of particular genes revealing their role in osteocyte function. Furthermore, evidence that Sost/sclerostin is expressed primarily in osteocytes and inhibits bone formation by osteoblasts, fueled research attempting to identify regulators of this gene as well as other osteocyte products that impact the function of osteoblasts and osteoclasts. The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits sclerostin expression generated a cascade of studies that revealed that osteocytes are crucial target cells of the actions of PTH. This review highlights these investigations and discusses their significance for advancing our understanding of the mechanisms by which osteocytes regulate bone homeostasis and for developing therapies for bone diseases targeting osteocytes.

13. For whom the bell tolls: Distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases

Review Article
Stavros C. Manolagas, A. Michael Parfitt

Abstract

Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar–canalicular system and mineralized matrix, osteocytes are ideally located throughout the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab.

14. Osteocyte control of osteoclastogenesis

Review Article
Charles A. O’Brien, Tomoki Nakashima, Hiroshi Takayanagi

Abstract

Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist sclerostin. However, the role of osteocytes in the control of bone resorption has been less clear. Recent studies have demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone. The goal of this review is to discuss these and other studies that reveal mechanisms whereby osteocytes control osteoclast formation and thus bone resorption.

References

  1. A. R. Stern and D. P. Nicolella, “Measurement and estimation of osteocyte mechanical strain,” Bone.
  2. W. Yao, W. Dai, J. X. Jiang, and N. E. Lane, “Glucocorticoids and Osteocyte Autophagy,” Bone.
  3. J. J. Wysolmerski, “Osteocytes remove and replace perilacunar mineral during reproductive cycles,” Bone.
  4. D. J. Webster, P. Schneider, S. L. Dallas, and R. Müller, “Studying osteocytes within their environment,” Bone.
  5. R. L. Jilka, B. Noble, and R. S. Weinstein, “Osteocyte apoptosis,” Bone.
  6. A. M. Nguyen and C. R. Jacobs, “Emerging role of primary cilia as mechanosensors in osteocytes,” Bone.
  7. J. Klein-Nulend, A. D. Bakker, R. G. Bacabac, A. Vatsa, and S. Weinbaum, “Mechanosensation and transduction in osteocytes,” Bone.
  8. K. Wesseling-Perry and H. Jüppner, “The osteocyte in CKD: New concepts regarding the role of FGF23 in mineral metabolism and systemic complications,” Bone.
  9. L. Lieben and G. Carmeliet, “Vitamin D signaling in osteocytes: Effects on bone and mineral homeostasis,” Bone.
  10. I. Kalajzic, B. G. Matthews, E. Torreggiani, M. A. Harris, P. Divieti Pajevic, and S. E. Harris, “In vitro and in vivo approaches to study osteocyte biology,” Bone.
  11. A. E. Loiselle, J. X. Jiang, and H. J. Donahue, “Gap junction and hemichannel functions in osteocytes,” Bone.
  12. T. Bellido, V. Saini, and P. D. Pajevic, “Effects of PTH on osteocyte function,” Bone.
  13. S. C. Manolagas and A. M. Parfitt, “For whom the bell tolls: Distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases,” Bone
  14. C. A. O’Brien, T. Nakashima, and H. Takayanagi, “Osteocyte control of osteoclastogenesis,” Bone.
  15. Bone remodelling in a nutshel June 22, 2012 by aviralvatsa
  16. Isolation of primary osteocytes from skeletally mature mice bones: Reoprt on “Isolation and culture of primary osteocytes from the long bones of skeletally mature and aged mice” (BioTechniques 52:361-373 ( June 2012) doi 10.2144/0000113876 )
  17. Nitric Oxide in bone metabolism July 16, 2012 by aviralvatsa
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Targeting bone turnover by nature-derived agents for deriving effective treatment of PCa metastases

Reporter: Ritu Saxena, Ph.D.

Introduction and basis of research: Prostate Cancer (PCa) is a leading cause of cancer-related deaths in the men of United States. Metastasis development results in high mortality rate in prostate cancer patients and PCa frequently metastasizes to the bone.

Using nature-derived agents, scientists at the Wayne State University School of medicine, Detroit, Michigan targeted bone remodeling – both bone formation and bone resorption, and proposed it as an effective strategy for the treatment of PCa bone metastasis. The treatment strategy was based on the recent observations pointing towards an increase in both osteoclastic activity and osteoblastic activity in PCa bone metastases which is contrary to the earlier belief that metastases is osteoblastic. Thus, authors designed a study targeting that both osteoclasts (bone forming cells) and osteoclasts (bone resorbing cells) activity for the treatment of PCa bone metastases

Study design: Li et al utilized formulated isoflavone and 3,39-diindolylmethane (BR-DIM) for the suppression of bone remodeling in PCa bone metastases. 3,39-diindolylmethane (DIM) is a natural agent mainly found in the members of the family Cruciferae such as broccoli, and Isoflavone is mainly found in soyabean. Isoflavone genistein has been reported to have the ability to inhibit cancer cell growth both in vitro and in vivo without toxicity. BR-DIM (manufactured by BioResponse, LLC.), as stated by the authors “could downregulate the expression of AR, Akt and NF-kB, leading to the inhibition of PCa growth and the induction of apoptosis in vitro”.  Authors thus, set out to test the hypothesis that “ a mixture of isoflavone and BR-DIM could inhibit the differentiation of osteoclasts and osteoblasts mediated through regulation of cellular signaling pathways that are involved in bone remodeling and PCa bone in vivo”.

A co-culture system involving pre-osteoclastic cell line-RAW264.7 cells, pre-osteoblastic cell line hFOB1.19, and several PCa cell lines, was established to determine how the PCa cells affect differentiation of bone cells. The effect of isoflavone and BR-DIM was then tested on both osteoclast and osteoblast differentiation and PCa cells in the co-culture system.

Results: Isoflavone and BR-DIM inhibited bone remodeling through the inhibition of cell signal transduction associated with osteoclast differentiation (RANKL-mediated signaling), osteoblast differentiation (RUNX2, periostin gene), and PCa growth and signaling. Isoflavone and BR-DIM, infact, were shown to affect multiple signaling pathways that could possibly be useful in the prevention of PCa progression especially in the context of bone metastases.

The study highlights an important message that natural agents could be a source for deriving agents that could be useful in the treatment of diseases such as cancer without toxicity issues.

Sources: Research Article – Li Y, Kong D, Ahmad A, Bao B, Sarkar FH. Targeting bone remodeling by isoflavone and 3,3′-diindolylmethane in the context of prostate cancer bone metastasis. PLoS One. 2012;7(3):e33011. http://www.ncbi.nlm.nih.gov/pubmed?term=22412975

UroToday report: http://www.urotoday.com/UroToday/Prostate-Cancer/targeting-bone-remodeling-by-isoflavone-and-3-3-diindolylmethane-in-the-context-of-prostate-cancer-bone-metastasis-beyond-the-abstract-by-fazlul-h-sarkar-phd-et-al.html

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Curator: Ritu Saxena, Ph.D.

Reporters: Ritu Saxena, Ph.D. and Dr. Venkat S. Karra, Ph.D.

Merck & Co. declared yesterday, July 12 2012, that it is ending a last-stage clinical trial of the osteoporosis drug Odanacatib based on the results demonstrating the effectively in reducing the post-menopausal fracture risk.

Safety and effectiveness of the drug were being evaluated in the trial enrolling more than 16,000 post-menopausal women and there was clear evidence that the drug was working. Hence, an independent committee decided to end the trial before completion. It was expected to continue until hip fractures had been reported in 237 patients. Merck said the interim analysis was conducted when around 70 percent of the targeted number of hip fractures had been reported. Merck said that it expects to target regulatory approval in the U.S., European Union and Japan in the first half of next year.

Odanacatib is designed to block cathepsin K, the major enzyme in osteoclasts that is responsible for breakdown of existing bone tissue. Osteoclasts, bone “eroding” cells along with bone forming cells, osteoblasts, are involved in bone turnover. In post menopausal osteoporosis, there is a decrease in bone turnover. Blocking the activity of osteoclasts would shift the equilibrium towards bone formation by relative increase in osteoblasts.

Earlier studies have performed 2-3 year long clinical trials showing its effectiveness in treating post-menopausal osteoporosis with a progressive increase in the bone mineral density, increase in bone formation markers expression in molecular studies and that it was generally well tolerated.. The oral drug, taken weekly, is considered more convenient than an older class of osteoporosis drugs known as bisphosphonates. Bisphosphonates, target osteoclasts and have shown to increase the risk of a severe bone disease, osteonecrosis of the jaw. Other safety concerns have also lead to the decline in the use of bisphosphonates.

Sales of Merck’s bisphosphonate drug Fosamax reached $3 billion in 2007, but that revenue has plunged since emergence of generic competition in early 2008. Wall Street analysts, on average, have forecast annual sales of odanacatib at $402 million by 2016, according to Thomson Pharma.

Source: http://www.dddmag.com/news/2012/07/merck-ends-odanacatib-study-early?et_cid=2744025&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2fnews%2f2012%2f07%2fmerck-ends-odanacatib-study-early

http://www.huffingtonpost.com/2012/07/12/odanacatib-osteoporosis-drug-fracture-bone_n_1666631.html

http://www.ncbi.nlm.nih.gov/pubmed/20740685

http://www.ncbi.nlm.nih.gov/pubmed/19874198

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Author: Aviral Vatsa, Ph.D., MBBS

Bone is a highly dynamic tissue that responds to changes in its external environment. Our bones adapt their mass and architecture according to the external mechanical loading conditions. Any long term alterations in loading conditions result in alteration of bone mass and architecture. This is highlighted in the following examples:

  1. Astronauts tend to lose their bone when they are in space. This is because the bones are not mechanically loaded externally due to absence of or reduction in gravitational force.
  2. Tennis players gain more mass in their playing forearm as compared to the non-playing forearm.

In both these examples bones tend to readjust their internal structural mass and alignment as per the external loads or their absence. How bones can achieve this? How bone forming and bone resorbing cells can be orchestrated to bring about this adaptation?

Bone cells

The questions mentioned above can be answered by knowing more about the cellular components of bone and their functions. Our bones primarily have four cell types: osteocytes, osteoblasts, osteoclasts and bone lining cells. Osteocytes are believed to be the ‘professional’ mechanosensors of bone i.e. they sense the external loads put on bone. Osteoblasts are the bone forming cells. Osteoclasts are the bone resorbing cells and as the name suggests, bone lining cells line the bone surfaces and play a role in regeneration of osteogenic cells. Osteocytes, following mechanical loading, secrete signalling molecules such as nitric oxide (besides others). These signalling molecules then modulate the activity of bone forming osteoblasts and/or bone resorbing osteoclasts. Thus osteocytes orchestrate this process wherein adequate bone mass and architecture is achieved in accordance with the external loading conditions.

Anatomically, the osteocytes reside with in the hard bony matrix. They are the majority cell types in bone and are ideally placed to sense the mechanical loads. Osteocytes have a cell body and from the cell body arise nearly fifty cell processes. Through these cell processes each osteocyte forms a network with the surrounding osteocytes. Through this network, following mechanical loading, osteocytes can stimulate the activity of osteoblasts and inhibit the activity of osteoclasts. This process of maintenance of bone mass and architecture is called bone remodelling. Bone remodelling occurs through out our life. It occurs in response to microfractures, which can appear in our bone without being noticed clinically. As long as our bone metabolism is physiologically normal these stimuli, such as microfractures, result in bone remodelling.

In diseases such as osteoporosis, the mechanism of bone remodelling is disrupted and there is more bone resorbtion than new bone formation thus leading to reduction in bone mass and alteration of bone architecture. Drug therapies for osteoporosis such as bisphosphonates, act by inhibiting the activity of osteoclasts thereby resulting in reduction in bone resorbtion and hence helping in maintenance of adequate bone mass and architecture. Newer therapies that target to modulate a part of bone remodelling are being investigated.

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Curator: Ritu Saxena, Ph.D.

News Brief:

Bone-protecting protein discovered

ABC Science, April 19, 2012.

A protein produced by bone cells could help in the development of better treatments for osteoporosis. Professor Hiroshi Takayanagi, of Tokyo Medical and Dental University, and colleagues, report their findings today in the journal Nature.

“I hope our discovery will lead to better treatment developments for osteoporosis, arthritis, or bone fractures,” says Takayanagi. The strength of our bones is controlled by hormones and by the balance between bone formation and breakdown (resorption).

If too much bone is broken down and not enough is made, bone density falls and the chance of fractures increases. Takayanagi and colleagues have found that bone forming cells, or osteoblasts, produce a protein called semaphorin 3A (Sema3A), which has previously been known to regulate nerve and immune cells. They found not only does Sema3A decrease bone breakdown but, unlike current osteoporosis medications that do the same, it also boosts bone formation at the same time.

Mouse studies

When they began their study, Takayanagi and colleagues already knew another protein produced by osteoblasts, called osteoprotegerin, decreases bone breakdown. But, the team suspected there would be other proteins that did the same.

The team checked the activity of proteins produced by osteoblasts from mice genetically engineered to have no osteoprotegerin, and found they were still inhibiting bone breakdown. They isolated the molecule responsible for this inhibition and using mass spectrometry identified it as Sema3A. The researchers then tested mice genetically engineered to have no functional Sema3A and found an increase in bone breakdown and a decrease in bone density.

Surprisingly, however, they also found that bone formation was also lower in these Sema3A knockout mice. In their final experiment they injected Sema3A into diseased mice and found it prevented further bone loss in osteoporosis and accelerated bone regeneration in the case of fractures.

“Many molecules regulate either resorption or formation but this is the first molecule that regulates both at the same time,” says Takayanagi.

http://www.abc.net.au/science/articles/2012/04/19/3480418.htm

‘Exciting discovery’

Dr Gethin Thomas of the Muscoskeletal Genetics Group at The University of Queensland Diamantina Institute welcomes the research. He says more 2 million Australians are currently affected by osteoporosis and half of women over the age of 50 are expected to suffer at least one osteoporotic fracture.

“The gold standard is to find therapies that can build bone as well as stop bone degradation, as osteoporosis is frequently only diagnosed after the bones have already become very weak,” says Thomas.

“This is a very exciting discovery identifying a completely new bone regulating pathway and one that is potentially very ‘druggable’.”

Sema3A is known to play important roles in the development of heart and nervous system, but researchers are yet understand exactly how the protein acts to boost bone formation and inhibit bone resorption. “It’s possible there might be side-effects on the heart or nerve generation but they haven’t explored that at all in this paper,” says bone cell biologist, Associate Professor Natalie Sims from the St Vincent’s Institute.

“It’s important that they’ve found this new factor and what it can do. What’s not clear is how specific it might be and that’s the obviously the next step they need to explore.”

http://www.abc.net.au/science/articles/2012/04/19/3480418.htm

Research:

Takanayagi et al published the research on Sema3a molecule’s bone formation and bone resorption activity in a recent issue of the journal Nature (2012). The research was summarized as:

The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine-based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/β-catenin signalling pathway. The osteopenic phenotype in Sema3a−/− mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases.

http://www.nature.com/nature/journal/v485/n7396/full/nature11000.html

Semaphorins have been known as one family of inhibitory axon guidance molecules. The semaphorins include secreted, transmembrane, and GPI anchored extracellular molecules that are involved in regulating axon guidance by inhibiting axons from growing toward incorrect targets. Semaphorin 3A (Sema3A) may play a particularly interesting role in limiting axon regeneration since it is expressed in meningeal fibroblasts that invade the injured spinal cord and surround the glial scar. In addition, the Sema3A co receptors, Neuropilin 1 and Plexin A1, are expressed on axons that regenerate up to the injured region, but do not cross this Sema3A containing region. Thus, Sema3A and its co receptors may have important roles in regulating axon guidance during neuronal development and after neuronal injury.

http://www.abcam.com/Semaphorin-3A-antibody-ab25999.html

Conclusion and Future perspective:

Takayanagi et al stated in the discussion of the article “Sema3A represents the long sought soluble molecule with the capacity to bring both osteoblasts and osteoclasts into a condition that favours bone mineral increase.”

Mone Zaidi and Jameel Iqbal, bone biology researchers from the Mount Sinai School of Medicine commented on the research stating “The protein Sema3A both restrains bone degradation and stimulates bone building in mice, suggesting a potential therapy for conditions such as osteoporosis”, referring to it as probable “double protection for weakened bones”.

http://www.nature.com/nature/journal/v485/n7396/full/485047a.html

Uncoupling of bone turnover (with a decrease in bone formation and an increase in bone resorption) has been observed in postmenopausal osteoporosis and microgravity-induced bone loss. Most of the available drugs are either anti-resorptive (For eg., bisphonsphonates), or anabolic (For eg., Parathyroid hormone) on bone. However, Sema3a might act as an effective therapeutic agent by targeting both bone formation and bone resorption.

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