Browse the corpus

Functioning as vital cells in the bone matrix that maintains adequate bone mineral density through stimulating bone turnover and maintaining plasma calcium levels, osteoclasts are multinucleate cells that arise from hematopoietic stem cells.[1][2][3][4] As a result, they are identifiable with the presence of CD13, CD14, and CD68 antigens and the lack of CD56, GrB, and Ki67 antigens.[5] When they become activated through their receptor activator nuclear factor-kB (RANK), they function primarily to resorb bone through various acids and collagenases. They have a complex interplay with the immune system, which can stimulate them and result in various pathologies.[1][2][3][6][7] Many bone diseases are associated with dysfunctional osteoclasts, such as osteoarthritis, osteoporosis, and osteopetrosis.[4][8][9][10]

The RANK-RANKL interaction is essential for osteoclastogenesis, and that interaction is under the regulation of osteoprotegerin (OPG). Osteoblasts and stromal cells secrete OPG, and it binds to RANKL on osteoblasts and stromal stem cells and prevents the interaction between RANKL and RANK, inhibiting osteoclastogenesis. This serves as a control mechanism to prevent excess bone resorption from taking place.[12] OPG opposes the effects of 1, 25-dihydroxy-vitamin D, parathyroid hormone (PTH), parathyroid hormone-related peptide (PTH-rP), and prostaglandin E2 (PGE), which all increase bone resorption.[6] Therefore, the interplay between RANK-RANKL-OPG is crucial in regulating osteoclastogenesis and the maintenance of bone mineral density and plasma calcium levels. Dysregulation of the RANK-RANKL-OPG system plays a vital role in the pathogenesis of many conditions, such as osteoporosis, osteopetrosis, and bone tumors. A complex interplay exists between the musculoskeletal and immune systems. Bone metabolism and immune activity are directly and indirectly connected, and immune system dysregulation can lead to osteoclast-mediated pathology. Two mechanisms can cause immune system-mediated osteoclast generation: T-cell mediated generation of osteoclasts and innate immune system generation of osteoclasts[2]: T-Cell Mediated Generation of Osteoclasts Similar to osteoblast expression of RANKL, arguably the most important osteoclast determining factor, activated T-cells also express RANKL. When there is a persistence of elevated active T-cells, it can lead to increased osteoclast differentiation, and ultimately, excess bone resorption. Additionally, active T-cells produce pro-inflammatory cytokines, which can stimulate the expression of RANKL on osteoblasts. Inflammatory cytokines that can stimulation osteoclast-mediated bone resorption are IL-1, IL-6, IL-11, IL-15, IL-17, and TNF-alpha. Additionally, IL-1 and TNF-alpha stimulate osteoblasts, which can cause RANKL-induced osteoclasts differentiation by the osteoblasts. Inflammatory cytokines that inhibit osteoclast-mediated bone resorption are IL-4, IL-10, IL-12, IL-13, IL-18, IFN-alpha, and GM-CSF. Innate Immune System Regulation of Osteoclasts

Additionally, active T-cells produce pro-inflammatory cytokines, which can stimulate the expression of RANKL on osteoblasts. Inflammatory cytokines that can stimulation osteoclast-mediated bone resorption are IL-1, IL-6, IL-11, IL-15, IL-17, and TNF-alpha. Additionally, IL-1 and TNF-alpha stimulate osteoblasts, which can cause RANKL-induced osteoclasts differentiation by the osteoblasts. Inflammatory cytokines that inhibit osteoclast-mediated bone resorption are IL-4, IL-10, IL-12, IL-13, IL-18, IFN-alpha, and GM-CSF. Innate Immune System Regulation of Osteoclasts Immune cells in the body have toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) on invading organisms, allowing the body to mount an immune response to the foreign organisms. Upon activation of the TLRs and immune cells, pro-inflammatory cytokines are produced, which can indirectly affect bone metabolism through activation of osteoclast differentiation, as previously mentioned. This is an indirect mechanism through which the innate immune system can cause osteoclast-mediated resorption of bone. Additionally, osteoclasts themselves have TLRs, which can be directly activated by foreign organisms. When TLRs on late osteoclast progenitors and osteoclasts are active, that increases the generation of osteoclasts. However, when TLRs on early osteoclast progenitors are activated, it decreases the generation of osteoclasts. This has been theorized to be the body’s way of preventing excess osteoclast generation. Aside from the interaction between the musculoskeletal and immune systems, the formation of many of the osteoclast structures previously described is important to prevent the malfunctioning of osteoclasts. For example, failure of the ruffled border to form may result in the failure of bone resorption.[3]