Bone remodeling mathematical models using advanced discretization techniques: A review
J. Belinha, R.M. Natal Jorge, J.C. Reis Campos, Mário A.P. Vaz, João Manuel, R.S. Tavares in Biodental Engineering V, 2019
Ruling both types of remodeling are a set of bone regulatory factors, such as insulin-like growth factors (IGF) I and II, transforming growth factor-β (TGF-β) superfamily, matrix metalloproteinases (MMPs), receptor activator of nuclear factor-Kb (RANK) and its cognate partner RANK ligand (RANKL), osteoprotegerin (OPG), fibroblast growth factor-2 (FGF-2) and bone morphogenetic proteins (BMPs). Among these, the RANKL/RANK/OPG system plays a key role in the control of bone resorption. When activated by RANKL, RANK causes differentiation of osteoclasts and promotes their function and survival (Cohen Jr., 2006; Teitelbaum and Ross, 2003; Xiao et al., 2016). However, OPG can bind to RANKL, preventing it from binding to RANK, which leads to an inhibition of osteoclastogenesis (Graves et al., 2011; Simonet et al., 1997). Thus, RANKL/OPG ratio expression ratio is a relevant indication of bone resorption. Regarding bone tissue formation, TGF-β is an important stimulator involved in osteoblastic differentiation and production of bone matrix (Bonewald and Dallas, 1994), as well as FGF-2 (Downey et al., 2009). Moreover, IGF I and II are responsible for controlling the number and function of osteoblasts (Cohick and Clemmons, 1993), as well as mediating the interaction between osteoblasts and osteoclasts (Mohamed, 2008).
Therapeutic approaches to bone protection in adulthood
Nicholas C. Harvey, Cyrus Cooper in Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Denosumab, a fully human antibody to receptor activator of nuclear factor kappa B ligand (RANKL) is a newer antiresorptive agent. RANKL, secreted by osteoblasts, is a major activator of osteoclastic bone resorption. Denosumab mimics the action of osteoprotegerin (OPG), the natural inhibitor of RANKL. It is administered as a subcutaneous injection once every 6 months and its efficacy has been demonstrated in patients with renal impairment, although due consideration should be given to the possibility of underlying renal bone disease in chronic kidney disease (CKD) 4–5. Three-year fracture data show a 68% reduction in vertebral fracture and 40% reduction in hip fracture (17). Side effects are uncommon, but may include skin rash and skin infections, predominantly cellulitis, not related to the time or site of injection. Hypocalcaemia can also be a risk, particularly if the patient is vitamin D deficient or has renal impairment.
Metabolic and endocrine bone disorders
Ashley W. Blom, David Warwick, Michael R. Whitehouse in Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Proliferation of osteoclastic progenitor cells requires the presence of an osteoclast differentiating factor produced by the stromal osteoblasts after stimulation by, for example, PTH, glucocorticoids or pro-inflammatory cytokines. It is now known that this ‘osteoclast differentiating factor’ is the receptor activator of nuclear factor-Ќβ ligand (RANKL for short), and that it has to bind with a RANK receptor on the osteoclast precursor in the presence of a macrophage colony-stimulating factor (M-CSF) before full maturation and osteoclastic resorption can begin. Osteoprotegerin (OPG), which is expressed by osteoblasts, is able to inhibit the differentiation of osteoclast precursors by preferentially binding with RANKL (acting as a ‘decoy’ receptor) and so reducing bone resorption by preventing RANKL from binding with its receptor on the osteoclast precursor. Pharmacological inhibition with denosumab which is a monoclonal RANKL antibody, leads to marked suppression of bone resorption and has been found to be a useful therapeutic agent for conditions like osteoporosis associated with generalized increases in resorption (see below). Use of denosumab to inhibit the RANK/RANKL/OPG system is also helpful in treating disorders associated with localized increases in bone resorption, including bone erosions associated with rheumatoid arthritis, Paget’s disease of bone, skeletal metastases particularly from breast and prostate cancer, and multiple myeloma.
Resveratrol promotes bone mass in ovariectomized rats and the SIRT1 rs7896005 SNP is associated with bone mass in women during perimenopause and early postmenopause
Published in Climacteric, 2023
X. Wang, C. Lu, Y. Chen, Q. Wang, X. Bao, Z. Zhang, X. Huang
The sirtuin family (Sirt1–7) is a group of NAD+-dependent deacetylases that play vital roles in oxidative stress. SIRT1 has been reported to promote longevity and decrease the incidence of many diseases, such as cancer, cardiovascular disease and diabetes. In animal experiments, activation of SIRT1 can delay and reduce the incidence of many age-related diseases, including osteoporosis [7–9]. Resveratrol, which is a small polyphenol compound found in various berries, nuts, grapes and other plants, is a natural activator of SIRT1 [10]. Bone mass is regulated by two major signaling pathways, receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) and Wnt/β-catenin [11], and imbalance in these systems can lead to osteoporosis. RANKL is produced by osteocytes to induce osteoclast differentiation/activation [12]. Osteoblasts produce OPG, which can bind to RANKL and block its interaction with RANK to prevent excessive bone resorption [13]. The Wnt/β-catenin signaling pathway regulates bone formation and OPG expression in osteoblasts [11].
Enamel matrix derivative does not affect osteoclast formation or bone resorption in cultures of mouse bone marrow macrophages or human monocytes
Published in Acta Odontologica Scandinavica, 2022
Susanne Lindquist, Catrine Isehed, Anita Lie, Pernilla Lundberg
Despite much effort to elucidate the mechanism, no consensus has been reached regarding how EMD affects periodontal tissue regeneration. However, in vitro studies demonstrate that EMD improves the behaviours of osteoblasts, endothelial cells, and periodontal ligament cells by affecting the cells’ attachment, spreading, proliferation, survival and expression of various transcription and growth factors [2,10,11]. Moreover, EMD upregulates the expression of osteoprotegerin (OPG) and downregulates receptor activator of nuclear factor-κβ ligand (RANKL) [11–13], which are key molecules in regulating the balance between bone resorption and bone formation under normal physiological conditions. RANKL is expressed by osteoblast lineage cells, and binds to its receptor (RANK) on osteoclast precursor cells of the monocyte/macrophage linage, thereby stimulating their differentiation into mature osteoclasts. OPG is produced by many cell types, including osteoblasts, and acts as a soluble decoy receptor for RANKL, preventing RANKL from binding to RANK and thereby inhibiting osteoclast formation and activity [11–13]. Overall, these data suggest that EMD may modulate the RANK-RANKL-OPG system towards bone formation.
PLD1 knockdown reduces metastasis and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis by modulating NF-κB and Wnt/β-catenin pathways
Published in Autoimmunity, 2021
Zhengyu Zhang, Xi Chen, Bo Gao, Guomin Sun, Yan Wang, Junke Wang, Ting Zhang, Hao Qian, Yu Zhang, Jun Huang, Rurong Sun, Jiabiao Wu, Lei Zhou
Intra-articular inflammatory transmitters not only directly stimulate synoviocytes and chondrocytes to synthesise collagenase, aggravating cartilage destruction, but also promote the high expression of receptor activator for nuclear factor-κ b ligand (RANKL) [23]. RANKL can activate inflammatory response transmitters, further activate the immune system, and aggravate immune damage in RA [23]. RANKL also leads directly to bone destruction by activating the NF-κB pathway [24]. In addition, the activation of the Wnt/β-catenin pathway also gives rise to synoviocyte proliferation, promotes synovial hyperplasia, increases bone damage, and disrupts joint function, which is also involved in regulating inflammatory reactions in synovial fibroblasts (SFS), and leads to their expression of inflammatory response transmitters, thereby mediating the inflammatory response in RA [17]. Therefore, inhibition of NF-κB and Wnt/β-catenin pathways may be critical for the treatment of RA. However, in this study, we found that PLD1 knockdown inhibit NF-κB and Wnt/β-catenin pathways. In addition, the results of experiments in a rat model of CIA also showed that PLD1 silencing was effective in alleviating CIA as well as arthritis-related parameters. Taken together, these results suggest that PLD1 inhibitors might function as an effective therapeutic strategy targeting RA.