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Equine June 2008 (Vol 3, No 5)

Abstract Thoughts — No Bones About It: A Lot Happens Inside Healthy Bone

by David J. Hurley, PhD

    Gay CV, Gilman VR, Sugiyama T. Perspectives on osteoblast and osteoclast function.

    Poult Sci 2000;79(7):1005-1008. Available online at ps.fass.org.


    We present evidence that the polar, matrix-forming osteoblasts are connected laterally to form an impervious layer of cells. Next, the possible mechanisms by which calcium ions are translocated across the layer of cells into sites of mineralization are analyzed. Finally, mechanisms of attachment of bone-resorbing osteoclasts are considered. Osteoclasts adhere to matrix, in part, through an arginine-glycine-aspartic acid-dependent mechanism. Adherence is under control of parathyroid hormone and 17β-estradiol.

    This abstract has been adapted with permission from The Poultry Science Association.


    When I (D.J.H.) was a bit younger and obtaining my PhD, I would regularly attend seminars concerning the biology of bone. A group of researchers at Pennsylvania State University, my favorite of whom was Carol Gay, was doing really interesting experiments to explain how and why bone worked. The article that we recommend in this column is by that same Carol Gay and is a review and perspective on the relationship among bone-forming cells, the mineralization of bone, and bone-degrading cells. Strong bone depends on lively and active cells that reside in the bone matrix. Osteoblasts (bone-forming cells) must form a healthy connected network to lay down the protein matrix and drive the mineralization process that gives bone its strength and capacity to absorb shock. In addition, osteoclasts (bone-degrading cells) must bind to sites in the matrix and proceed to undo the work of osteoblasts by degrading the protein network and demineralizing the bone. Osteocytes, the third cell type in bone, have a more mysterious role but appear to be derived from osteoblasts and be the master regulator of building and tearing down bone. If bone is left "static" for too long, the hydroxyapatite (essentially, calcium phosphate) crystals become tightly aligned and the protein matrix weakens, leaving it brittle.

    Bone is an unusually dynamic tissue, contrary to its appearance. It regularly renews at a rapid rate, and its maximal strength and function depend on its renewal. Bone growth and repair are directly mediated by the formation of a "solid wall" of osteoblasts that regulate both the deposition of matrix protein and bone mineralization. Osteoblasts function by forming a tightly associated, essentially impervious sheet of cells that defines the fluid compartment of bone. To build bone, osteoblasts first secrete a mixture that is approximately 85% collagen protein; the remaining 15% consists of a combination of osteopontin, osteonectin, bone sialoprotein, and osteocalcin, with a little proteoglycan thrown into the mix. Then the osteoblasts deliver calcium to the matrix for mineralization by using sodium-calcium exchange pumps and calcium-ATPase pumps to move calcium from areas of lower concentration in the fluid phase of bone to areas of higher concentration on the matrix. On the matrix, calcium-containing crystals form and are aligned to maximize bone strength.

    Because the calcium-rich crystals in bone become realigned in a fashion that reduces bone strength and durability, calcium must be released from bone matrix and replaced on a regular basis to optimize bone strength and function. Bone is also used as a long-term calcium "depot" in the body, and calcium release may also be mediated by other functions, such as milk production in mares. Osteoclasts remove calcium from the matrix to allow reformation of bone, are derived from monocytes, and migrate in bone. Osteoclasts have even been called the innate immune cells of the bone.1 The function of osteoclasts is altered by signals from innate and adaptive immune cells. Osteoclasts carry several immune receptors and are responsive to microbial ligands through Toll-like receptors and cytokines.2 Osteoclasts must adhere to specific sites that provide signals for their activation. Adherence to many of the sites is induced by integrin recognition—a common signal regulating the movement of inflammatory cells from the circulation into the tissue. Integrin signals that promote binding of osteoclasts routinely contain an amino acid pattern, arginine-glycine-aspartic acid, that provides the main cue for osteoclasts to attach to the bone matrix. Expression of additional receptors for osteoclast binding, such as CD44 (a hyaluronic acid receptor), is under the control of hormones such as parathyroid hormone and estradiol. When bound, osteoclasts are activated and release enzymes that demineralize bone and release matrix components.

    The assembly of bone collagen matrix has been studied in bone and in laboratory models. These collagen assemblies have been reviewed by Guille and coworkers.3 In this review, the authors compared model systems for building bone-like matrix with computer-enhanced three-dimensional images of demineralized bone. It appears that the release of collagen from osteoblasts establishes a self-assembling pattern that extends away from the osteoblast "wall" in space. Similar structures can be built in a laboratory by directed delivery of collagen subunits in a contained space at a high concentration. These structures pass from an essentially liquid crystal state through a gel phase to form a structure that mimics bone.

    Vitamin D3 and transforming growth factor-b (TGF-β) have been shown to have an age-dependent effect on osteoblast growth.4 The pro-proliferative responses of vitamin D3 and TGF-β were shown to be directly correlated to the dose of the compound in cell cultures from young adult rats (approximately 3 months of age), but cells derived from older rats (approximately 15 months of age) were not responsive to either factor. This is an important problem related to maintaining the bones of aging animals because vitamin D3 is an important modulator of calcium uptake and mobilization in the body and because TGF-β modulates the growth and differentiation of cells of immune origin in muscle and in connective tissue.

    The growth or repair of bone is subject to a variety of influences, such as the satellite cells of muscle.5 As stem cells differentiate into muscle, they lose their ability to modify bone formation and degradation. Once satellite cells begin to express the MyoD and Pax7 genes associated with muscle differentiation, the cells have lost their capacity to influence bone growth and repair. What is particularly exciting about this is that muscle stem cells may provide a treatment to enhance bone healing in difficult cases in the future.6

    So it is clear that keeping bone healthy is a multifactorial process that involves precise timing and many factors in the environment of the bone. A good question to ask about this process could be borrowed from singer Avril Lavigne: "Why'd you have to go and make things so complicated?" Well, it seems it's just nature's way.

    1. Wu Y, Humphrey MB, Nakamura MC. Osteoclasts: the innate immune cells of the bone. Autoimmunity 2008;41(3):183-194.

    2. Bar-Shavit Z. Taking a toll on the bones: regulation of bone metabolism by innate immune regulators. Autoimmunity 2008;41(3):195-203.

    3. Giraud Guille MM, Mosser G, Helary C, Eglin D. Bone matrix like assemblies of collagen: from liquid crystals to gels and biomimetic materials. Micron 2005;36:602-608.

    4. Shiels MJ, Mastro AM, Gay CV. The effect of donor age on the sensitivity of osteoblasts to the proliferative effects of TGFβ and 1,25(OH2) vitamin D3. Life Sci 2002;70:2967-2975.

    5. Hashimoto N, Kiyono T, Wada MR, et al. Osteogenic properties of human myogenic progenitor cells. Mech Dev 2008;125(3-4):257-269.

    6. Usas A, Huard J. Muscle-derived stem cells for tissue engineering and regenerative therapy. Biomaterials 2007;28(36):5401-5406.

    References »

    NEXT: Death of Eight Belles Turns Spotlight on Racehorse Health and Safety


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