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Osteoblasts are colloquially referred to as cells that "build" bone. These cells are directly responsible for osteogenesis (or ossification). Osteoblasts synthesize and deposit organic bone matrix (osteoid) proteins that will mineralize in both developing skeletons and during the process of bone remodeling that occurs continuously throughout an individual's life.[1] Bone is approximately 10% water, 30% organic, and 60% inorganic. The organic component is approximately 85 to 90% collagen (primarily type 1 -resisting tensile forces), proteoglycans (resisting compressive forces), non-collagenous proteins (osteocalcin and osteonectin) and glycoproteins (osteopontin). The inorganic component, or mineralized matrix, is composed of hydroxyapatite crystals [Ca10(PO4)6(OH)2] that provides protection and support while serving as the body's repository for calcium and phosphate.[2][3][4][5] Osteoblasts also indirectly regulate osteoclast formation and bone remodeling by cell-cell contact, paracrine signaling, and cell-bone matrix interaction.[6][7] Osteoblasts derive from two embryonic populations of mesenchymal stromal cells (or mesenchymal stem cells, MSCs). MSCs originating from the neural ectoderm can directly differentiate into osteoprogenitor cells that will become osteoblasts and form bone through intramembranous ossification (i.e., squamous bones of the calvaria and clavicle). MSCs originating from the paraxial mesoderm differentiate into axial skeleton osteoblasts, while the MSCs of the lateral plate mesoderm form osteoblasts of the appendicular skeleton. The axial and appendicular skeleton develop by endochondral ossification, with these osteoblasts deriving from intermediate perichondral cells or hypertrophic chondrocytes. Both the indirect and direct processes converge at osteoprogenitor cells (or preosteoblasts).[8] Osteoblasts are induced from the osteoprogenitor cells by numerous signals. Understanding of the osteogenic lineage remains incomplete.[9]

To fully understand the implication of physiologic disturbance of osteoblasts in various disease states, one must have a perfunctory understanding of bone and the often-overlooked nuances of this dynamic skeletal organ. Overview of Osseous Components Bone (osseous tissue) Hard, dense connective tissue that gives structural support to the body Cortical (compact) bone Dense, outer cortex that supports and protects, the main store of calcium, accounts for 80% of bone mass, formed of osteons. Cancellous (trabecular) bone Porous, highly vascular "spongy" internal tissue with a high surface area to volume ratio. Comprised of trabeculae. 20% bone mass, almost 10x the surface area of cortical bone. Red and yellow bone marrow fills in space between pores Periosteum Covers the external surface of cortical bone and is a dense fibrous sheath containing osteoprogenitor cells. An exception is over articular surfaces, where articular cartilage is found. Periosteal cells are capable of becoming osteoblasts Endosteum Covers innermost cortical bone and is often only one cell thick. The endosteum lines the medullary cavity. This cell layer also contains osteoprogenitor cells that can differentiate into osteoblasts Osteon (Haversian System) The fundamental anatomical and functional unit of cortical bone; cylindrically arranged and typically parallel to the long axis. Area of remodeling in cortical bone Consists of concentric lamellae surrounding a central Haversian canal, which permit blood vessels and nerves to travel within and supply the osteon Volkmann's canals are perpendicular perforating channels in lamellar bone that permit blood vessels and nerves to reach the Haversian canal from the periosteal and endosteal surface; these also interconnect the osteon canals Interstitial lamellae Remnants of partially resorbed osteons from previous remodeling Trabecula The main anatomical and functional unit of cancellous bone. Aligned towards mechanical load distribution. Bone marrow is contained within the porosities created by the trabeculae Bone Marrow Colloquially divided into "red" bone marrow (Medulla ossium rubra): active myeloid tissue where hemopoietic stem cells produce red blood cells; and "yellow" bone marrow (Medulla ossium flava): hematopoietically inactive, mesenchymal stem cells (stroma) that accumulate lipids

The main anatomical and functional unit of cancellous bone. Aligned towards mechanical load distribution. Bone marrow is contained within the porosities created by the trabeculae Bone Marrow Colloquially divided into "red" bone marrow (Medulla ossium rubra): active myeloid tissue where hemopoietic stem cells produce red blood cells; and "yellow" bone marrow (Medulla ossium flava): hematopoietically inactive, mesenchymal stem cells (stroma) that accumulate lipids As individuals age, the red marrow becomes yellow as the fat concentration increases. Yellow marrow can revert to red under physiologic stress requiring hemopoiesis.[27][5][28][29] Physiology of Remodeling Remodeling is a process orchestrated by bone multicellular units (BMUs), a term for aggregates of osteoblasts and osteoclasts that function sequentially to remodel bone. Estimates are that 1 million BMUs are active at any time. BMUs consist of a cutting cone of osteoclasts that resorb bone, and osteoblasts that subsequently fill in the resorption area. The process predominately divides into four phases: activation, resorption, reversal, and formation. Activation recruits osteoclasts Resorption osteoclasts "catabolize" or resorb bone In the reversal stage, osteoclasts undergo apoptosis and osteoblasts are recruited Osteoblasts then secrete a matrix in the Formation stage that mineralizes [30] Location of Remodeling Eighty percent of estimated bone remodeling activity has been demonstrated on cancellous bone surfaces. Cortical bone demonstrates intracortical remodeling in addition to remodeling on the periosteal and endocortical surfaces.[31] Signaling While not completely understood, bone and bone-forming cells exhibit many complex signaling mechanisms. MSCs initially differentiate into osteoprogenitor cells, triggered by core-binding factor alpha-1 (CBFA1) or runt-related transcription factor 2 (RUNX2).[32][33][34] With RUNX2 activated, the cells become osteoprogenitor (or preosteoblast) cells. Under the influence of bone morphogenic proteins (BMPs), insulin-like growth factor-1, -2 (IL-1, IL-2), Osterix, as well as other growth factors, the osteoprogenitor cells become osteoblasts.[33][35][36][37][38] Mature osteoblasts also produce receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF) which regulate further osteoblast differentiation into osteoclasts.[39][40]

MSCs initially differentiate into osteoprogenitor cells, triggered by core-binding factor alpha-1 (CBFA1) or runt-related transcription factor 2 (RUNX2).[32][33][34] With RUNX2 activated, the cells become osteoprogenitor (or preosteoblast) cells. Under the influence of bone morphogenic proteins (BMPs), insulin-like growth factor-1, -2 (IL-1, IL-2), Osterix, as well as other growth factors, the osteoprogenitor cells become osteoblasts.[33][35][36][37][38] Mature osteoblasts also produce receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF) which regulate further osteoblast differentiation into osteoclasts.[39][40] Several signaling pathways that are imperative to maintaining a balance between osteoblast and osteoclasts include WNT, BMP, PTH/PTHrP, Notch, and Hedgehog.[41] Furthermore, growth factors, and anabolic hormones (including fibroblast growth factor, insulin-like growth factor, interleukin-6, parathyroid hormone, estrogen, and calcitonin) exhibit anti-apoptotic effects on osteoblasts. Tumor necrosis factor, glucocorticoids, and bone morphogenic protein 2 induce apoptosis in osteoblasts.[10] WNT/β-Catenin (Canonical WNT) Pathway The cell-membrane Frizzled receptor and co-receptor low-density lipoprotein receptor-related protein 5 (LRP5) are inactive in the absence of Wnt ligands. Without Wnt, β-catenin is phosphorylated by glycogen synthase kinase-3 (GSK-3), signaling it for proteolysis by ubiquitin-dependent proteases. The Wnt pathway is activated when Wnt binds Frizzled and LRP5. GSK-3 downregulates. Inactivation of GSK-3 increases the accumulation of intracellular β-catenin. β-catenin subsequently translocates to the nucleus and induces gene transcription that results in an increase in bone mass through a variety of different mechanisms.; this includes stem cell renewal, preosteoblast replication, osteoblastogenesis, and inhibiting osteoblast apoptosis. Other secreted inhibitors, such as Dickkopf (Dkk) and Sclerostin (SOST), also can regulate signaling through the Wnt/Frizzled/LRP5 interaction.[30][41][42][43][44]

The Wnt pathway is activated when Wnt binds Frizzled and LRP5. GSK-3 downregulates. Inactivation of GSK-3 increases the accumulation of intracellular β-catenin. β-catenin subsequently translocates to the nucleus and induces gene transcription that results in an increase in bone mass through a variety of different mechanisms.; this includes stem cell renewal, preosteoblast replication, osteoblastogenesis, and inhibiting osteoblast apoptosis. Other secreted inhibitors, such as Dickkopf (Dkk) and Sclerostin (SOST), also can regulate signaling through the Wnt/Frizzled/LRP5 interaction.[30][41][42][43][44] Sclerostin, for example, is secreted from terminally differentiated osteoblasts (osteocytes) embedded within the newly formed bone matrix. Sclerostin binds to and inhibits LRP5 from binding to frizzled receptors. This process activates the Wnt pathway and increases bone production.[41][43] Parathyroid Hormone (PTH) & Parathyroid Hormone Related Peptide (PTHrP) Pathways PTH and PTHrP are distinct polypeptides that serve separate biological functions, though functioning through a common receptor -the family B G-protein-coupled-receptor parathyroid hormone-1 receptor (PTH1R). PTH targets osteoblasts and renal tubular cells while PTHrP targets chondrocytes, osteoblasts, placental cells, skin, hair follicles, brain, and teeth. Notably, PTH functions to maintain calcium and phosphate homeostasis while PTHrP is involved in the development of the placenta, fetus, and bone.[45] PTH stimulates both resorption and formation of bone depending on the temporality of its exposure. Continuous elevation results in resorption, while intermittent elevation leads to osteoblast formation. Both effects appear to result from the modulation of PTH1R. Resorption may result from increased RANKL synthesis and inhibiting OPG mRNA expression, while the PTH induced mechanism for bone formation has not been completely elucidated.[46][47]

PTH stimulates both resorption and formation of bone depending on the temporality of its exposure. Continuous elevation results in resorption, while intermittent elevation leads to osteoblast formation. Both effects appear to result from the modulation of PTH1R. Resorption may result from increased RANKL synthesis and inhibiting OPG mRNA expression, while the PTH induced mechanism for bone formation has not been completely elucidated.[46][47] There have been suggestions that intermittent elevation of PTH results in the release of TGF-B from resorbing bone that, in the absence of stimulation, serves to recruit osteogenic progenitors. PTH is also an upstream regulator of Runx2. The cell cycle effect of PTH on Runx2 appears to be mediated through MAP kinase ERK1/2 phosphorylation, activation of CREB/fos with JunD, resulting in the expression of IL-11 and suppression of Dkk as well as cyclin D1 activity to increase bone formation.[8][45] PTH stimulates osteoblasts to produce angiopoietin 1, a vascular growth factor as well as WNT co-receptor LRP6 and activates WNT signaling.[47] PTH also reduces SOST levels in bone, as does skeletal loading.[46] Sodium-Hydrogen exchanger regulatory factor (NHERF) 1 also has been implicated in modulating PTH signaling.[48] The mechanisms, as mentioned earlier, could serve to contribute to skeletal manifestations of individuals with kidney or parathyroid disorders.[49][50][51]