How bone becomes mechanically optimised for its function Flashcards
(27 cards)
1.Bone structure and functions
Bone is a mineralized connective tissue, with 99% of the total calcium in the body stored as calcium phosphate salts in bones, that provide phsiological functions that provide support; movement; protection; blood cell production; storage and acts as an endocrine organ.
- Basal bone remodelling mechanisms
The bone remodelling is a complex mechanism that involves continuously replacing and renewing of bone structure. About 10% of adult bone is turned over each year. It is primarily characterized by the bone-forming osteoblast, which produces the organic bone matrix and aids its mineralisation; the bone-degrading osteoclast that dissolves the bone mineral and enzymatically degrades extracellular matrix proteins; and the osteocyte, an osteoblast-derived post-mitotic cell within the bone matrix that acts as a mechanosensor and an endocrine cell. The bone lining cell is thought to have a specific role in coupling bone resorption to bone formation, perhaps by physically defining bone remodelling compartments.
Details of bone remodeling
The bone remodelling cycle is comprised of three phases: (1) initiation of bone resorption by osteoclasts, (2) the transition from resorption to new bone formation, and (3) the bone formation by osteoblasts. Osteoblasts lay down the organic matrix of bone, composed of collage and proteoglycans. Calcium phosphate salts precipitate on the collagen fibres, ultimately forming hydroyapatite crystals. Some of the osteoblasts become trapped within the bone and are then known as osteocytes. The osteocytes and osteobalsts are connected by long processes,running in tiny canals throughout the bone, and form a continuous network of very large surface area running throughout the bone and over its furface. They separate the bone fluid adjacent to the bone surface, which is high in calcium, from the ECF on the other side. This is achieved by the combination of the osteoclasts, osteoblasts, osteocytes and osteoblast-derived post-mitotic cell form the temporary anatomical structure called basic multicellular unit. (BMU)
Osteoblasts: differentiation and function
Osteoblasts differentiation is achived by the converted expression of a number of key transcrption factors, and bone formation by osteoblasts is controlled both locally and systemically during bone modelling in development and throughout life. Studies of dieseases associated with defects in bone formation,such as developmental limb disorders and high bone mass conditins, have demonstrated the crucial importance of lcoal bone formation control by bone morphogenetic protein and wingless signalling pathways for osteobalst differentiation and function. In the adult, BMP2 can act as a potent stimulator of ectopic bone formation and it is used clinically to enchance bone formation, for example, during fracture repair.
3.Endocrine regulation of bone remodelling
To change the balance between rosion and deposition, the endocrine system involving parathyroid hormone (PTH), calcitonin, vitamin D3 and drivatives, and oestrogen. The first three hormones played an essential role in the calcium homeostasis which requires pricise control on serum calcium level. (2.4 mM)
Calcitonin
The calcitonin acts through its receptors that are expressed specifically on osteoclasts and directly inhibits osteoclastic resorption, shifting the balance in favour of deposition.
PTH
PTH binds to its receptors, that are expressed on osteoblasts and bone marrow stromal cells, in which, through signalling by cAMP responsive element binding protein (CREB), it activates expression of MCSF and RANKL, thereby indirectly stimulating osteoclastic bone resorption. The PTH also acts on the kidney to enhance the calcium resorption and gut to increase absoption via action on vitamin D3.
vitamin D3
The vitamin D3 indirectly affect the bone structure through maintainence of calcium homeostasis. In children, a dietary lack of vitamin D3 is the commonest cause of rickets. Plasma calcium do not drop substantially because of PTH secretion, which erodes the bones to maintain plasma levels, but the weakened bones become distored. An adult version of rickets is known as osteomalacia.
Oestrogen
The major role for ostrogen in the skeletal system is as a bone-sparing hormone that acts through receptors expressed by both osteoclasts and osteoblasts. This sex hormone is crucial in the control of osteoclasts lifespan, and can cause pre-osteoclast and osteoclast apoptosis through Fas and Fas ligand signalling. Therefore, loss of oestrogen in women after menopause results in increased osteoclast formation and survival. Oestrogen also blocks osteoclast function indirectly through effects on the immune system and has a role in regulating the response of bone to mechanical stimulation.
4.Bone repair mechanisms
The mechanisms of bone repair begin with hematoma formation, where a blood clot and fibrin mesh are created at the injury site. This initial phase is followed by the formation of a fibrocartilaginous callus, characterized by the deposition of osteoid, the development of granulation tissue, and the activity of fibroblasts. Next, the bony callus forms as the osteoid undergoes mineralization, a process visible on an X-ray. Finally, bone remodeling occurs, refining the newly formed bone and restoring its original structure.
- Mechanoadaptive responses at the cellular level (mechanostat theory)
The mechanostat theory outlined how postnatal load-bearing bones alter their mass and confomation in relation to changing mechanical demands. The role within bone’s four mechanoadaptive pathways: 1) formation modeling and 2) targeted modleing, which occur with heightened mechanical loading, 3) resorption modeling, and 4) disuse-mediated remodeling, which occur with disuse. These four pathways regulate whole-bone stiffness in response to changing mechanical demands.
Formational modelling overview
At cellular level, formational modelling suggests osteocyte perturbation by mechanical loading introduces osteoblastic bone fomation on a surface. The mechanical loading of bone above customary levels results in deformation of the mineralized matrix, which is hypothesized to produce interstitial fluid pressure gradients within the network of caves and tunnels that are home to osteocyte and their cytoplasmic processes- the lacunar-canalicular system.
Formational modelling mechanism
Previous studies have suggested that rapid movement of interstitial fluid throughout the lacunar-canalicular system stimulates osteocytes via shear stress generated along their cell membranes and hoop strains where integrins tether osteocytes cytoplasmic proecesses to the surrounding bone matrix.
Osteocyte surface molecules and structures such as integrins, primary cilia, G protein-coupled receptors, and ion channels are proposed to act in concert to sense these mechanical cues and convert the machanical stimuli into cellular signals that alter gene expression.
In response to mechanical stimuli, osteocyte intracellular calcium signaling is initiated, along with secretion of pro-osteoblast paracrine factors such as NP and IGF-1. These factors promote the osteoblst recruitment, proliferation and differentiation necessary to mount a bone formation response.
This mechanical loading also suppresses osteoblastic paracrine signaling but also suppresses osteocyte secretion of sclerostin which , a Wnt antagonists and negative regulator of osteoblastic bone formation.
Result for formational modelling
Overall, this mechanical stimulation results in new bone formation through both secretion of pro-osteoblast factors and suppressionof negative regulators of bone formation.This formation modelingcan increae the thickness of exisiting trabecular elements and icnrease cortical thicknesses at the diaphysis of long bones through bone deposition on the endocortical and periosteal surfaces.
Target remodelling overview
Targeted remodelling suggests microcracks generated during loading stimulate osteocyte apoptosis and targeted removal of bone by osetoclasts and subsequent formation of bone by osteoblasts.
Targeting modelling mechanism
Osteocyte apoptosis can be triggered as early as 24 h after fatigue loading and microdamage induction, followed by secretion of proosteoclastic factors, osteoclast recritment, and intracortical resorption approximately 10 to 14 d later, focused primarily at regions containing linear microcraks. The apoptotic osteocytes are not themselves the main source of pro-osteoclastic factors necessary for osteoclastogenesis. It is the neighboring viable osteocytes which promote the osteoclastogenesis necessary for initiating intracortical remodelling. In turn, the osteoclastic resorption and subsequent formation by osteoblasts replace fatigue-damaged tissue and promote extension of the fatigue life of the skeletal structure.
Conclusion for targeted modelling and formational modelling
Collectively, the targeted remodeling and formation modeling that accompany greater than customary strain stimuli can result in a wider bone due to periosteal expansion, thicker cortices due to endocortical depostion, and increased intracortical porosity due to remvoal of fatigue damage.
Disuse-mediated remodeling overview
The disuse-mediated modelling suggests osteocyte apoptosis with disuse stimulates bone resorption and coupled formation which also depicted is the negative bone balance within each remodeling unit that can accompany disuse-mediated remodelling.
Experimental evidence for disuse-mediated remodelling
The disuse-mediated modelling suggests osteocyte apoptosis with disuse stimulates bone resorption and coupled formation which also depicted is the negative bone balance within each remodeling unit that can accompany disuse-mediated remodelling.
Profound bone resorption can accompany inadequate mechanical stimulation, with reports from animal studies of 12% cortical bone loss after 8 wk of limb isolation in turkets, and in dogs decrements of almost half of baseline metaphyseal bone mass after 60 weeks of limb casting were observed.
Conclusion for disuse-mediated remodelling
Similar to the bone loss that precedes bone formation in the process of targeted remodeling, bone loss with disuse appears to be initiated by osteocyte apoptosis. In conditions of disuse, patterns of bone loss include thinning or complete removal of trabecular elements, increased intracortical porosity, expansion of the marrow space, and thinning of the cortices. As with heightened loading, periods of unloading of the skeleton can result in both a remodeling and a modeling response. The first response, disuse-mediated remodeling, results in increased intracortical porosity due to an imbalance between osteoclast and osteoblast activity within each remodeling unit. The results of this imbalance are larger osteons with less infill and more residual porous space and overall net bone loss within the skeleton. This disuse-mediated remodeling and resulting porosity preferentially occur at the endocortical region in diaphyseal bone.
Resorption modeling overview
Resorption modeling suggests the disuse-mediated osteocyte apoptosis stimulates osteoclastic bone resorption on a surface. It involves independent osteoclast activity around the marrowcavity that ultimately expands the marrow cavity and thins the cortices. Novel image registration techniques were used to demonstrate that the endocortical expansion by osteoclasts with unloading occurs where osteoblasts are least active on existing endocortical surfaces. The potential extent of endocortical-specific resorption modeling has been demonstrated in animal studies, with reports of over 9% endocortical volume expansion after 3 wk of muscle paralysis and 12% reduction in cortical cross-sectional area, due primarily to endocortical expansion, after 12 wk of limb isolation (35).
Conclusion for the disuse-mediated remodeling
Together, the disuse-mediated remodeling that results in intracortical porosity, and the resorption modeling responsible for marrow expansion and thinning of the cortices (Figs. 3C, D) rid the bone of excess mass and decrease the stiffness of the structure in response to the new, lower than customary strain stimuli.
Conclusion for the disuse-mediated remodeling and the resorption model
Together, the disuse-mediated remodeling that results in intracortical porosity, and the resorption modeling responsible for marrow expansion and thinning of the cortices (Figs. 3C, D) rid the bone of excess mass and decrease the stiffness of the structure in response to the new, lower than customary strain stimuli.
- Leg weakness pathology in broiler chickens overview
Imbalance of bone maturation was also shown in broiler chicken. Broiler farming is popular worldwide due to the fast growth and production cycle of chicken. However, the fast growth rate disrupts the original balance of tissue growth and development in broilers with reduced tibua density and bone minearal content. (M.T.Shim et al. 2011) Due to rapid weight gain and delayed skeletal development, skeletal diseases inluding tibia dyschondroplasia, especially in the leg bones occurr in broilers.
