The Role of Calcium in the Bone Homeostasis and in Skeletal Muscle Regulation (Think of the Role of Hormones and Events During Muscle Contraction)
The best-known feature of skeletal muscle is its ability to contract and cause movement. Skeletal muscles act not only to produce movement but also to stop movement, such as resisting gravity to maintain posture. Small, constant adjustments of the skeletal muscles are needed to hold a body upright or balanced in any position. Muscles also prevent excess movement of the bones and joints, maintaining skeletal stability and preventing skeletal structure damage or deformation. Joints can become misaligned or dislocated entirely by pulling on the associated bones; muscles work to keep joints stable.
A first aspect of the coupling principle is provided by the direct control of osteoclastogenesis by cells of the osteoblast lineage. Indeed, as outlined earlier in the chapter, osteoblasts and stromal cells have been known for many years to control bone degradation by expressing M-CSF, required for the proliferation of osteoclast precursors, and RANKL, mediating the differentiation of hematopoietic osteoclast precursors toward mature multinucleated cells (osteoclastogenesis). Osteoblasts also express OPG, the soluble decoy receptor that binds to RANKL and prevents it from binding to RANK, thus providing a negative control mechanism to limit osteoclast formation (see earlier). Recently, new findings obtained by using conditional mouse models added to this mechanism that osteocytes are also crucial players in the regulation of osteoclast formation, as they appear to be major sources of RANKL driving osteoclast formation and activation during adult bone remodeling. Other mechanisms by which osteoblast lineage cells control osteoclastogenesis in vivo are being increasingly uncovered, through the use of cell type- and/or stage-specific mutagenesis in mice. For instance, the non-canonical Wnt pathway (Wnt signaling relayed to intracellular responses by mechanisms that are independent of β-catenin actions) between osteoblast-lineage cells and osteoclast precursors appears to regulate bone resorption. Osteoblast-lineage cells express Wnt5a, which activates non-canonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins such as Ror2, expressed by osteoclast precursors. As a result of this Wnt5a-Ror2 signaling, RANK expression was found to increase and osteoclastogenesis was enhanced.275 Another newly identified mechanism involves osteoblastic expression of semaphorin 3A (Sema3A), a member of the family of secreted and membrane-associated axon guidance molecules that use plexins and neuropilins (Nrp) as their primary receptors; soluble Sema3A produced by osteoblasts was found to exert an osteoprotective effect by inhibiting osteoclast precursor differentiation through the Plexin-A coreceptor Nrp1. In contrast, Sema6D signaling through the receptor Plexin-A on osteoclasts was previously found to promote osteoclast formation and function. Hence, this system’s complexity with multiple interacting ligands and receptors calls for further studies to clarify their precise roles in osteoblast-osteoclast communication.
Calcium as a nutrient is most commonly associated with the formation and metabolism of bone. Over 99 percent of total body calcium is found as calcium hydroxyapatite (Ca10[PO4]6[OH]2) in bones and teeth, where it provides hard tissue with its strength (Hadjidakis DJ, 2006). Calcium in the circulatory system, extracellular fluid, muscle, and other tissues is critical for mediating vascular contraction and vasodilatation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion. Bone tissue serves as a reservoir for and source of calcium for these critical metabolic needs through the process of bone remodeling. Calcium metabolism is regulated in large part by the parathyroid hormone (PTH)–vitamin D endocrine system, which is characterized by a series of homeostatic feedback loops. The rapid release of mineral from the bone is essential to maintain adequate levels of ionized calcium in serum. During vitamin D deficiency states, bone metabolism is significantly affected as a result of reduced active calcium absorption. This leads to increased PTH secretion as the calcium sensing receptor in the parathyroid gland senses changes in circulating ionic calcium. Increased PTH levels induce enzyme activity (1α-hydroxylase) in the kidney, which converts vitamin D to its active hormonal form, calcitriol. In turn, calcitriol stimulates enhanced calcium absorption from the gut. Not surprisingly, the interplay between the dynamics of calcium and vitamin D often complicates the interpretation of data relative to calcium requirements, deficiency states, and excess intake (Halloran BP, 1980).
In fact, the capacity for movement is a property of all cells but, with the exception of muscle, these movements are largely restricted to intracellular events. Skeletal muscles, the major focus of this chapter, permit us to interact with our external environment in an amazing number of ways, and they also contribute to our internal homeostasis.
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Hadjidakis DJ, Androulakis II. Bone Remodeling. Annals of the New York Academy of Sciences 1092 (Women's Health and Disease: Gynecologic, Endocrine, and Reproductive Issues). 2006:385–96.
Halloran BP, DeLuca HF. Calcium transport in small intestine during pregnancy and lactation. American Journal of Physiology. 1980;