Most people think that the skeleton is a static structure - like a pillar of plaster. But the bone is continuously remodelling, and the bone surface moves in and out. Bone physiology is on another time scale than other organs - such as the heart or lungs. The Basic Multicellular Unit (BMU) is a wandering team of cells that dissolves an area of the bone surface and then fills it with new bone.
Don't miss the "continue" and "start" buttons in these Flash animations.
New! These animations have been redrawn to show the vascular canopy which was described several years ago, and reviewed in a recent paper by Eriksen.
The BMU remodeling sequence | ||
|---|---|---|
| Phase | Factors | Description |
Origination | (+) PTH, IGF, IL-1, IL-6, PGE, calcitriol, TNF, NO
(-) estrogen | After microdamage to the bone, following mechanical stress, following exposure to some cytokines, or at random, a BMU will originate. The osteocytes secrete messages to the surface cells. A circulatory canopy is formed from the lining cells. |
Osteoclast recruitment |
(+) RANK-ligand, M-CSF
(-) osteoprotegerin (OPG), GM-CSF 
click to see movie | Stromal cells that have been activated by messages from osteocytes or IL-1, PTH, calcitriol, etc (but not IL-6) will then produce M-CSF (macrophage colony stimulating factor) which stimulates differentiation of cells into pre-osteoclasts. The stromal cells also divide to produce pre-osteoblasts, which express RANK-ligand (RANK-L) on their cell surfaces. Pre-osteoclasts have membrane receptors called RANK, related to the TNF family. When RANK-L activates these receptors the cells fuse and differentiate into mature multinucleared osteoclasts which develop a ruffled border and resorb bone. Meanwhile, OPG is a free-floating decoy receptor, made by mature osteoblasts, which can bind the RANK-L. |
Resorption | (+) Integrins, some interleukins, acidosis, vitamin A
(-) estrogen, calcitonin, interferon, TGF, other interleukins, sFRP-1 | The mature osteoclasts resorb bone by forming a space on the matrix surface and secreting hydrogen ions and cathepsin into the space. As the BMU wanders, new osteoclasts are continuously activated and then start resorption. At any one spot on the surface the resorption lasts about two weeks. The osteoclasts then undergo programmed cell death or apoptosis, which is delayed by estrogen deficiency. |
Osteoblast recruitment | (+) Wnt, BMPs, IGF, FGFs, PDGFs, CSF, PTH, calcitriol, Runx2, GST-RANK-Ligand, TGF-beta
(-) ? leptin | Osteoblasts are derived from marrow stromal cells, which can differentiate into either adipocytes or osteoblasts; the transcription factor Runx2 (previously named Cbfa1) is necessary for osteoblastic differentiation. Osteoblasts are probably attracted by bone-derived growth factors. Wnt-signalling and bone morphogenic proteins are important, and osteocytes tonically secrete sclerostin which inhibits Wnt-signalling. |
Osteoid formation | (+) TGF-beta, BMPs, IGF
(-) FGFs, PDGFs, glucocorticoids | The active, secreting osteoblasts then make layers of osteoid and slowly refil the cavity. They also secrete growth factors, osteopontin, osteocalcin, osteoprotegerin and other proteins. |
Mineralization | (+) calcium, phosphate
(-) pyrophosphate | When the osteoid is about 6 microns thick, it begins to mineralize. This process, also, is regulated by the osteoblasts. Osteoblasts also primarily regulate phosphate metabolism through PHEX and FGF-23, whose mechanisms of action are still uncertain. Osteoblast life-span is regulated by estrogens and other hormones. |
Mineral maturation | Other ions | For months after the cavity has been filled with bone, the crystals of mineral are packed more closely and the density of the new bone increases. |
Quiescence | The final osteoblasts turn into lining cells which participate in the minute-to-minute release of calcium from the bones. Some of the osteoblasts also turn into osteocytes which remain in the bone, connected by long cell processes which can sense mechanical stresses to the bones. | |
A photomicrograph of bone showing osteoblasts and osteoclasts together in one Bone Metabolic Unit
Watch animations of the bone remodeling sequence.
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Updated 3/30/07
