Osteoblast-Osteoclast Communication and Bone Homeostasis
Total Page：16
File Type：pdf, Size：1020Kb
cells Review Osteoblast-Osteoclast Communication and Bone Homeostasis Jung-Min Kim 1, Chujiao Lin 1, Zheni Stavre 1, Matthew B. Greenblatt 2 and Jae-Hyuck Shim 1,3,* 1 Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; [email protected] (J.-M.K.); [email protected] (C.L.); [email protected] (Z.S.) 2 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA; [email protected] 3 Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA * Correspondence: [email protected]; Tel.: +1-508-856-6245 Received: 25 August 2020; Accepted: 8 September 2020; Published: 10 September 2020 Abstract: Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P,SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts. Keywords: bone; osteoblast; osteoclast; bone remodeling 1. Introduction Bone is a dynamic tissue that remodels continuously throughout life, providing mechanical support for stature and locomotion and protecting vital organs such as bone marrow and the brain [1]. Bone also functions as a reservoir for calcium and phosphate. Continuous remodeling is required to preserve both of these critical functions by preventing accumulation of bone damage and maintaining both the mechanical strength of bone and calcium homeostasis [2,3]. Bone remodeling is a process in which old or damaged bone is removed by osteoclasts and replaced with new bone formed by osteoblasts. Osteoclasts, bone-resorbing cells, originate from hematopoietic stem cells (HSCs) [4–8] and degrade bone via secretion of acid and proteolytic enzymes, such as cathepsin K (CTSK), that dissolve collagen and other matrix proteins during bone resorption [9,10]. Osteoblasts, bone-forming cells, arise from the commitment of mesenchymal precursors to osteoprogenitor lineages through the sequential action of transcriptional factors and terminally differentiate into osteocytes [11–14]. Osteoblasts produce extracellular proteins, including osteocalcin, alkaline phosphatase and type I collagen, the latter of which makes up over 90% of bone matrix protein. The extracellular matrix is first secreted as unmineralized osteoid and subsequently mineralized through the accumulation of calcium phosphate in the form of hydroxyapatite [15]. The sequential strategies of osteoclastogenesis and osteoblastogenesis are shown in Figure1. Cells 2020, 9, 2073; doi:10.3390/cells9092073 www.mdpi.com/journal/cells Cells 2020, 9, 2073 2 of 14 Cells 2020, 9, x 2 of 14 (a) Osteoclastogenesis (b) Osteoblastogenesis FigureFigure 1. 1. StrategiesStrategies of of osteoclastogenes osteoclastogenesisis and and osteoblastogenesis. osteoblastogenesis. (a (a) )Osteoclastogenesis. Osteoclastogenesis. Osteoclasts Osteoclasts areare tissue-specific tissue-specific macrophages macrophages derived derived from from hemato hematopoieticpoietic stem stem cells. cells. In In the the presence presence of of M-CSF, M-CSF, hematopoietichematopoietic stem stem cells cells are are committed committed to to macrop macrophagehage colony-forming colony-forming units units (CFU-M), (CFU-M), the the common common precursorprecursor cells cells of of macrophages andand osteoclasts.osteoclasts. WhenWhen activated activated by by the the RANKL-RANK RANKL-RANK signal, signal, CFU-M CFU- is Mfurther is further differentiated differentiated into mononucleated into mononucleated osteoclasts osteoclasts and subsequently and subsequently fuse to become fuse multinucleated to become multinucleatedosteoclasts. Multinucleated osteoclasts. Multinucleated osteoclasts are osteoclasts fully matured are uponfully amatured cognate upon interaction a cognate with interaction osteoblasts withand osteoblasts resorb bone and matrix resorb by secretingbone matrix acids by (H secreting+), proteases acids (e.g., (H+), CTSK) proteases and matrix(e.g., CTSK) metalloproteinases and matrix metalloproteinases(MMPs) when they (MMPs) have a tightwhen junction they have between a tigh thet junction bone surface between and basalthe bone membrane surface of and osteoclasts basal membraneto form a sealedof osteoclasts compartment to form and a seal thened osteoclasts.compartment (b )and Osteoblastogenesis. then osteoclasts. ( Osteoblastsb) Osteoblastogenesis. are derived Osteoblastsfrom multipotent are derived mesenchymal from multipotent precursors mese and theynchymal are committed precursors to and osteoprogenitors they are committed and further to osteoprogenitorsdifferentiated into and osteoblastic further diffe lineagerentiated through into the osteoblastic expression lineage of transcription through factorsthe expression RUNX2 andof transcriptionOsterix. They factors are continued RUNX2 and to di Osterix.fferentiation They into are co matrix-producingntinued to differentiation mature osteoblasts into matrix-producing and these cells maturehave di osteoblastsfferent fates: and apoptosis, these cells bone have lining different cells or fate osteocytes.s: apoptosis, A subpopulation bone lining ofcells mature or osteocytes. osteoblasts A is subpopulationsurrounded by unmineralizedof mature osteoblasts osteoid and is further surro diundedfferentiated by unmineralized into osteocytes, terminallyosteoid and diff erentiatedfurther differentiatedbone cells in mineralizedinto osteocytes, bone. terminally differentiated bone cells in mineralized bone. BoneBone remodeling remodeling is istraditionally traditionally considered considered to be to composed be composed of four offour sequential sequential phases phases [16]: the [16 ]: activationthe activation phase phase when when osteoclast osteoclast progenitors progenitors are arerecruited recruited to todamaged damaged bone bone surface; surface; resorption resorption phasephase when when mature mature osteoclasts osteoclasts resorb resorb damaged damaged bone; bone; reversal reversal phase phase when when osteoclasts osteoclasts die die and and osteoblastosteoblast progenitors progenitors are are recrui recruited;ted; formation formation phase phase when when mature mature osteoblasts osteoblasts produce produce new new bone bone matrixmatrix (osteoid) (osteoid) and and this this matrix matrix is is mineralized mineralized [17,18]. [17,18]. Almost Almost all all new new bone bone formation formation is is observed observed in in areasareas with with previous previous resorption resorption and and in in distinct distinct an anatomicalatomical structures structures called called basic basic multicellular multicellular units units (BMUs)(BMUs) [19]. [19 ].The The balance balance between between osteoblast-media osteoblast-mediatedted bone bone formation formation and osteoclast-mediated and osteoclast-mediated bone resorption is tightly regulated without a major alteration in a net bone mass or mechanical strength under homeostatic conditions [2]. However, dysregulation of this balance results in abnormal bone Cells 2020, 9, 2073 3 of 14 Cells 2020, 9, x 3 of 14 bone resorption is tightly regulated without a major alteration in a net bone mass or mechanical remodeling, resulting in both postmenopausal and secondary forms of osteoporosis, such as diabetes- strength under homeostatic conditions [2]. However, dysregulation of this balance results in abnormal associated and glucocorticoid-induced osteoporosis [20–22]. In addition to improving understanding bone remodeling, resulting in both postmenopausal and secondary forms of osteoporosis, such as of the bone resorption and formation phases, a more detailed study on the reversal phase might be diabetes-associated and glucocorticoid-induced osteoporosis [20–22]. In addition to improving necessary as reversal step dysfunction is associated with pathologic bone loss [23,24]. understanding of the bone resorption and formation phases, a more detailed study on the reversal In this review, we illustrate the key mediators that control the cross-talk between osteoblasts and phase might be necessary as reversal step dysfunction is associated with pathologic bone loss [23,24]. osteoclasts through cell–cell contact or secretory factors (Figure 2). In this review, we illustrate the key mediators that control the cross-talk between osteoblasts and osteoclasts through cell–cell contact or secretory factors (Figure2). FigureFigure 2. Key mediatorsmediators ofof osteoblast-osteoclast osteoblast-osteoclast interaction. interaction. Osteoblast-osteoclast Osteoblast-osteoclast communications communications are areessential essential for fine-tuningfor fine-tuning of bone of remodelingbone remodeling during boneduring homeostasis.