Regulatory cellular and molecular networks in the bone microenvironment during aging

Abstract

Age-induced abnormalities in bone metabolism disrupt the equilibrium between bone resorption and formation. This largely stems from disturbances in bone homeostasis, in which signaling pathways exert a significant regulatory influence. Aging compromises the functionality of the bone marrow mesenchymal stem cells (BMSCs), ultimately resulting in tissue dysfunction and pathological aging. Age-related bone degradation primarily manifests as reduced bone formation and the increased accumulation of bone marrow fat. Cellular senescence diminishes bone cell vitality, thereby disrupting the balance of bone remodeling. Intensive osteoclast differentiation leads to the generation of more osteoclasts and increased bone resorption. This review provides insight into the impact of aging on bone, encompassing bone cell states during the aging process and bone signaling pathway transformations. It primarily delves into aging-related signaling pathways, such as the bone morphogenetic protein/Smad, Wnt/β-catenin, osteoprotegerin/receptor activator of NF-κB ligand/receptor activator of NF-κB, connexin43/miR21, and nuclear factor erythroid 2-related factor 2/antioxidant response element pathways, seeking to enhance our comprehension of crucial bone cells and their secretory phenotypes during aging. Furthermore, the precise molecular regulatory mechanisms underlying the interactions between bone signaling pathways and aging are investigated.

Keywords

senescence / bone marrow mesenchymal stem cells / osteoblast / osteoclast / osteocyte

References

[1] DiLoreto R , Murphy CT . The cell biology of aging. Mol Biol Cell 2015; 26: 4524- 31.

[2] Asscher VER , Waars SN , van der Meulen-de Jong AE , et al. Deficits in geriatric assessment associate with disease activity and burden in older patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2022; 20: e1006- 21.

[3] Buck DW 2nd , Dumanian GA . Bone biology and physiology: Part I. The fundamentals. Plast Reconstr Surg 2012; 129: 1314- 20.

[4] Taipaleenmäki H . Regulation of bone metabolism by microRNAs. Curr Osteoporos Rep 2018; 16: 1- 12.

[5] Boskey AL , Coleman R . Aging and bone.J Dent Res 2010; 89: 1333- 48.

[6] He C , He W , Hou J , et al. Bone and muscle crosstalk in aging. Front Cell Dev Biol 2020; 8: 585644.

[7] Carnovali M , Banfi G , Mariotti M . Age-dependent modulation of bone metabolism in zebrafish scales as new model of male osteoporosis in lower vertebrates. GeroScience 2021; 43: 927- 40.

[8] Al-Bari AA , Al Mamun A . Current advances in regulation of bone homeostasis. FASEB bioAdvances 2020; 2: 668- 79.

[9] Liu J , Ding Y , Liu Z , et al. Senescence in mesenchymal stem cells: functional alterations, molecular mechanisms, and rejuvenation strategies. Front Cell Dev Biol 2020; 8: 258.

[10] Farr JN , Fraser DG , Wang H , et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res 2016; 31: 1920- 9.

[11] Zhou J , Zhang Z , Joseph J , et al. Biomaterials and nanomedicine for bone regeneration: progress and future prospects. Exploration (Beijing) 2021; 1: 20210011.

[12] Schurman CA , Verbruggen SW , Alliston T . Disrupted osteocyte connectivity and pericellular fluid flow in bone with aging and defective TGF-β signaling. Proc Natl Acad Sci USA 2021; 118: e2023999118.

[13] Hwang ES . Senescence suppressors: their practical importance in replicative lifespan extension in stem cells. Cell Mol Life Sci 2014; 71: 4207- 19.

[14] Liu ZZ , Hong CG , Hu WB , et al. Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3. Autophagy 2021; 17: 2766- 82.

[15] Onal M , Piemontese M , Xiong J , et al. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem 2013; 288: 17432- 40.

[16] Ramakrishnan A , Torok-Storb B , Pillai MM . Primary marrowderived stromal cells: isolation and manipulation. Methods Mol Biol 2013; 1035: 75- 101.

[17] Zou Z , Li H , Yu K , et al. The potential role of synovial cells in the progression and treatment of osteoarthritis. Exploration (Beijing) 2023; 3: 20220132.

[18] Ren X , Hu B , Song M , et al. Maintenance of nucleolar homeostasis by CBX4 alleviates senescence and osteoarthritis. Cell Rep 2019; 26: 3643- 56.e7.

[19] Infante A , Rodríguez CI . Osteogenesis and aging: lessons from mesenchymal stem cells. Stem Cell Res Ther 2018; 9: 244.

[20] Weng Z , Wang Y , Ouchi T , et al. Mesenchymal stem/stromal cell senescence: hallmarks, mechanisms, and combating strategies. Stem Cells Transl. Med. 2022; 11: 356- 71.

[21] Khayrullin A , Krishnan P , Martinez-Nater L , et al. Very long-chain C24:1 ceramide is increased in serum extracellular vesicles with aging and can induce senescence in bone-derived mesenchymal stem cells. Cells 2019; 8: 37.

[22] Idris AI , Sophocleous A , Landao-Bassonga E , et al. Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab 2009; 10: 139- 47.

[23] Sakurai M , Ishitsuka K , Ito R , et al. Chemically defined cytokinefree expansion of human haematopoietic stem cells. Nature 2023; 615: 127- 33.

[24] Ribatti D , Nico B , Vacca A . Multiple myeloma as a model for the role of bone marrow niches in the control of angiogenesis. Int Rev Cell Mol Biol 2015; 314: 259- 82.

[25] Mikkola HK , Orkin SH . The journey of developing hematopoietic stem cells. Development (Cambridge, England) 2006; 133: 3733- 44.

[26] Méndez-Ferrer S , Michurina TV , Ferraro F , et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466: 829- 34.

[27] Le PM , Andreeff M , Battula VL . Osteogenic niche in the regulation of normal hematopoiesis and leukemogenesis. Haematologica 2018; 103: 1945- 55.

[28] de Haan G , Lazare SS . Aging of hematopoietic stem cells. Blood 2018; 131: 479- 87.

[29] Mohrin M , Shin J , Liu Y , et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science (New York) 2015; 347: 1374- 7.

[30] Flohr Svendsen A , Yang D , Kim K , et al. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 2021; 138: 439- 51.

[31] Yu B , Huo L , Liu Y , et al. PGC-1α controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell 2018; 23: 193- 209.e5.

[32] Xu C , Wang J , Zhu T , et al. Cross-talking between PPAR and WNT signaling and its regulation in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther 2016; 11: 247- 54.

[33] Khosla S . Pathogenesis of age-related bone loss in humans. J Gerontol A Biol Sci Med Sci 2013; 68: 1226- 35.

[34] Kim HJ , Kim WJ , Shin HR , et al. ROS-induced PADI2 downregulation accelerates cellular senescence via the stimulation of SASP production and NFκB activation. Cell Mol Life Sci 2022; 79: 155.

[35] Duque G , Troen BR . Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome. J Am Geriatr Soc 2008; 56: 935- 41.

[36] Bragdon B , Thinakaran S , Moseychuk O , et al. Casein kinase 2 beta-subunit is a regulator of bone morphogenetic protein 2 signaling. Biophys J 2010; 99: 897- 904.

[37] Navas-Enamorado I , Bernier M , Brea-Calvo G , et al. Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle. Ageing Res Rev 2017; 37: 39- 52.

[38] Finkel T , Deng CX , Mostoslavsky R . Recent progress in the biology and physiology of sirtuins. Nature 2009; 460: 587- 91.

[39] Kanfi Y , Naiman S , Amir G , et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 2012; 483: 218- 21.

[40] Chen P , Hu B , Xie LQ , et al. Scara3 regulates bone marrow mesenchymal stem cell fate switch between osteoblasts and adipocytes by promoting Foxo1. Cell Prolif 2021; 54: e13095.

[41] Aobulikasimu A , Liu T , Piao J , et al. SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Sci Rep 2023; 13: 7991.

[42] Grootaert MOJ , Finigan A , Figg NL , et al. SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis. Circ Res 2021; 128: 474- 91.

[43] Lai P , Song Q , Yang C , et al. Loss of Rictor with aging in osteoblasts promotes age-related bone loss. Cell Death Dis 2016; 7: e2408.

[44] Liu J , Liang C , Guo B , et al. Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging. Aging Cell 2017; 16: 360- 76.

[45] Mostoslavsky R , Chua KF , Lombard DB , et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006; 124: 315- 29.

[46] Zhang DM , Cui DX , Xu RS , et al. Phenotypic research on senile osteoporosis caused by SIRT6 deficiency. Int J Oral Sci 2016; 8: 84- 92.

[47] Buenzli PR , Sims NA . Quantifying the osteocyte network in the human skeleton. Bone 2015; 75: 144- 50.

[48] Schaffler MB , Cheung WY , Majeska R , et al. Osteocytes: master orchestrators of bone. Calcif Tissue Int 2014; 94: 5- 24.

[49] McClung MR , Grauer A , Boonen S , et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014; 370: 412- 20.

[50] Tiede-Lewis LM , Xie Y , Hulbert MA , et al. Degeneration of the osteocyte network in the C57BL/6 mouse model of aging. Aging (Milano) 2017; 9: 2190- 208.

[51] Dou Z , Ghosh K , Vizioli MG , et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 2017; 550: 402- 6.

[52] Wang Y , Xu L , Wang J , et al. Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro. Int J Mol Med 2021; 47: 76.

[53] Quinn JM , Elliott J , Gillespie MT , et al. A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. Endocrinology 1998; 139: 4424- 7.

[54] Walsh MC , Kim N , Kadono Y , et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol 2006; 24: 33- 63.

[55] Kim HN , Chang J , Iyer S , et al. Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice. Aging Cell 2019; 18: e12923.

[56] Almeida M , Han L , Martin-Millan M , et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 2007; 282: 27285- 97.

[57] Piemontese M , Almeida M , Robling AG , et al. Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight 2017; 2: e93771.

[58] Yang W , Nagasawa K , Münch C , et al. Mitochondrial sirtuin network reveals dynamic SIRT3-dependent deacetylation in response to membrane depolarization. Cell 2016; 167: 985- 1000.e21.

[59] Ye Z , Hu C , Wang J , et al. Burst of hopping trafficking correlated reversible dynamic interactions between lipid droplets and mitochondria under starvation. Exploration (Beijing) 2023; 3: 20230002.

[60] Glancy B , Hartnell LM , Malide D , et al. Mitochondrial reticulum for cellular energy distribution in muscle. Nature 2015; 523: 617- 20.

[61] Dudley HR , Spiro D . The fine structure of bone cells. J Biophys Biochem Cytol 1961; 11: 627- 49.

[62] Park-Min KH . Metabolic reprogramming in osteoclasts. Semin Immunopathol 2019; 41: 565- 72.

[63] Yan C , Shi Y , Yuan L , et al. Mitochondrial quality control and its role in osteoporosis. Front Endocrinol 2023; 14: 1077058.

[64] Holtrop ME , King GJ . The ultrastructure of the osteoclast and its functional implications. Clin Orthop Relat Res 1977; 123: 177- 96.

[65] Farr JN , Almeida M . The spectrum of fundamental basic science discoveries contributing to organismal aging. J Bone Miner Res 2018; 33: 1568- 84.

[66] Almeida M , Laurent MR , Dubois V , et al. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 2017; 97: 135- 87.

[67] Zeng R , Faccio R , Novack DV . Alternative NF-κB regulates RANKL-induced osteoclast differentiation and mitochondrial biogenesis via independent mechanisms. J Bone Miner Res 2015; 30: 2287- 99.

[68] Ucer S , Iyer S , Kim HN , et al. The effects of aging and sex steroid deficiency on the murine skeleton are independent and mechanistically distinct. J Bone Miner Res 2017; 32: 560- 74.

[69] Bain G , Müller T , Wang X , et al. Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. Biochem Biophys Res Commun 2003; 301: 84- 91.

[70] Simonet WS , Lacey DL , Dunstan CR , et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309- 19.

[71] Lowery JW , Rosen V . The BMP pathway and its inhibitors in the skeleton. Physiol Rev 2018; 98: 2431- 52.

[72] Chen G , Xu H , Yao Y , et al. BMP signaling in the development and regeneration of cranium bones and maintenance of calvarial stem cells. Front Cell Dev Biol 2020; 8: 135.

[73] Zhang XY , Chen YP , Zhang C , et al. Icariin accelerates fracture healing via activation of the WNT1/β-catenin osteogenic signaling pathway. Curr Pharm Biotechnol 2020; 21: 1645- 53.

[74] Zhu Y , Xu F , Yan X , et al. The suppressive effects of aluminum chloride on the osteoblasts function. Environ Toxicol Pharmacol 2016; 48: 125- 9.

[75] Ma C , Gao J , Liang J , et al. HDAC6 inactivates Runx2 promoter to block osteogenesis of bone marrow stromal cells in age-related bone loss of mice. Stem Cell Res Ther 2021; 12: 484.

[76] Xu F , Zhang K , Grunstein M . Acetylation in histone H3 globular domain regulates gene expression in yeast. Cell 2005; 121: 375- 85.

[77] Nakashima K , Zhou X , Kunkel G , et al. The novel zinc fingercontaining transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002; 108: 17- 29.

[78] Nakashima K , de Crombrugghe B . Transcriptional mechanisms in osteoblast differentiation and bone formation. Trends Genet 2003; 19: 458- 66.

[79] Wu X , Tu X , Joeng KS , et al. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell 2008; 133: 340- 53.

[80] Soen S . Control of inflammatory bone destruction by targeting the Wnt signaling pathway. Clin Calcium 2019; 29: 337- 41.

[81] Lin GL , Hankenson KD . Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem 2011; 112: 3491- 501.

[82] Coulson J , Bagley L , Barnouin Y , et al. Circulating levels of dickkopf-1, osteoprotegerin and sclerostin are higher in old compared with young men and women and positively associated with whole-body bone mineral density in older adults. Osteoporos Int 2017; 28: 2683- 9.

[83] Williams BO , Insogna KL . Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res 2009; 24: 171- 8.

[84] Wang J , Yang J , Cheng X , et al. Influence of calcium supplementation against fluoride-mediated osteoblast impairment in vitro: involvement of the canonical Wnt/β-catenin signaling pathway. J Agric Food Chem 2019; 67: 10285- 95.

[85] Manolagas SC , Almeida M . Gone with the Wnts: beta-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol 2007; 21: 2605- 14.

[86] Hsu MN , Huang KL , Yu FJ , et al. Coactivation of endogenous Wnt10b and Foxc2 by CRISPR activation enhances BMSC osteogenesis and promotes calvarial bone regeneration. Mol Ther 2020; 28: 441- 51.

[87] Rauner M , Sipos W , Pietschmann P . Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation. Age (Dordrecht) 2008; 30: 273- 82.

[88] Bennett CN , Longo KA , Wright WS , et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 2005; 102: 3324- 9.

[89] Chen X , Li L , Guo J , et al. Treadmill running exercise prevents senile osteoporosis and upregulates the Wnt signaling pathway in SAMP6 mice. Oncotarget 2016; 7: 71072- 86.

[90] Gardinier JD , Al-Omaishi S , Morris MD , et al. PTH signaling mediates perilacunar remodeling during exercise. Matrix Biol 2016; 52-54: 162- 75.

[91] Wang F , Yang G , Li Y , et al. A peptide from wheat germ abolishes the senile osteoporosis by regulating OPG/RANKL/RANK/TRAF6 signaling pathway. Phytomedicine 2022; 104: 154304.

[92] Nagy V , Penninger JM . The RANKL-RANK Story. Gerontology 2015; 61: 534- 42.

[93] Udagawa N , Koide M , Nakamura M , et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab 2021; 39: 19- 26.

[94] Bian Y , Hu T , Lv Z , et al. Bone tissue engineering for treating osteonecrosis of the femoral head. Exploration (Beijing) 2023; 3: 20210105.

[95] Abdi S , Binbaz RA , Mohammed AK , et al. Association of RANKL and OPG gene polymorphism in arab women with and without osteoporosis. Genes 2021; 12: 200.

[96] Wang XF , Zhang YK , Yu ZS , et al. The role of the serum RANKL/OPG ratio in the healing of intertrochanteric fractures in elderly patients. Mol Med Rep 2013; 7: 1169- 72.

[97] Matsumoto T , Endo I . RANKL as a target for the treatment of osteoporosis. J Bone Miner Metab 2021; 39: 91- 105.

[98] Scheiber MD , Liu JH , Subbiah MT , et al. Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause (New York) 2001; 8: 384- 92.

[99] Giaginis C , Tsantili-Kakoulidou A , Theocharis S . Peroxisome proliferator-activated receptors (PPARs) in the control of bone metabolism. Fundam Clin Pharmacol 2007; 21: 231- 44.

[100] Hooshiar SH , Tobeiha M , Jafarnejad S . Soy isoflavones and bone health: focus on the RANKL/RANK/OPG pathway. Biomed Res Int 2022; 2022: 8862278.

[101] Tousen Y , Ichimaru R , Kondo T , et al. The combination of soy isoflavones and resveratrol preserve bone mineral density in hindlimbunloaded mice. Nutrients 2020; 12: 2043.

[102] Zakłos-Szyda M , Budryn G , Grzelczyk J , et al. Evaluation of isoflavones as bone resorption inhibitors upon interactions with Receptor Activator of Nuclear Factor-κB Ligand (RANKL). Molecules (Basel) 2020; 25: 206.

[103] Park K , Ju WC , Yeo JH , et al. Increased OPG/RANKL ratio in the conditioned medium of soybean-treated osteoblasts suppresses RANKL-induced osteoclast differentiation. Int J Mol Med 2014; 33: 178- 84.

[104] Zhang J , Fujita Y , Chang L , et al. Beneficial effects of anti-RANKL antibody in depression-like phenotype, inflammatory bone markers, and bone mineral density in male susceptible mice after chronic social defeat stress. Behav Brain Res 2020; 379: 112397.

[105] Nakamura T , Matsumoto T , Sugimoto T , et al. Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab 2014; 99: 2599- 607.

[106] Troib A , Guterman M , Rabkin R , et al. Endurance exercise and growth hormone improve bone formation in young and growth-retarded chronic kidney disease rats. Nephrol Dial Transplant 2016; 31: 1270- 9.

[107] Pichler K , Loreto C , Leonardi R , et al. RANKL is downregulated in bone cells by physical activity (treadmill and vibration stimulation training) in rat with glucocorticoid-induced osteoporosis. Histol Histopathol 2013; 28: 1185- 96.

[108] Eghbali-Fatourechi G , Khosla S , Sanyal A , et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003; 111: 1221- 30.

[109] Cao J , Venton L , Sakata T , et al. Expression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice. J Bone Miner Res 2003; 18: 270- 7.

[110] Kim HN , Xiong J , MacLeod RS , et al. Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence. JCI Insight 2020; 5: e138815.

[111] Kim N , Odgren PR , Kim DK , et al. Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci USA 2000; 97: 10905- 10.

[112] Sun YX , Xu AH , Yang Y , et al. Role of Nrf2 in bone metabolism. J Biomed Sci 2015; 22: 101.

[113] Vono R , Jover Garcia E , Spinetti G , et al. Oxidative stress in mesenchymal stem cell senescence: regulation by coding and noncoding RNAs. Antioxid Redox Signal 2018; 29: 864- 79.

[114] Bivi N , Condon KW , Allen MR , et al. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res 2012; 27: 374- 89.

[115] Davis HM , Pacheco-Costa R , Atkinson EG , et al. Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging Cell 2017; 16: 551- 63.

[116] Kubben N , Zhang W , Wang L , et al. Repression of the antioxidant NRF2 pathway in premature aging. Cell 2016; 165: 1361- 74.

[117] Hou Y , Dan X , Babbar M , et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 2019; 15: 565- 81.

RIGHTS & PERMISSIONS

The Author(s). Published by Oxford University Press on behalf of Higher Education Press.