TABLE 4.
Specific roles of MMPs under physiological conditions in bone remodeling.
| Entity | MMP | Role | References |
| Cartilage and bone cells | Network of multiple MMPs (mainly widely expressed MMP-2, -7, -9, -12, -13, -14, -16) | Maintain bone and cartilage health by their normal proteolytic activity. | Everts et al., 1992; Meikle et al., 1992; Mattot et al., 1995; Apte et al., 1997; Johansson et al., 1997; Bord et al., 1998; Jimenez et al., 1999; Filanti et al., 2000 |
| Control bone tissue remodeling at the levels of osteocyte viability and activities, osteoclast recruitment and function, bone matrix solubilization, coupling of bone resorption and formation, osteoblast recruitment and survival, cell-extracellular matrix interaction, and cell–cell interaction. | Blavier and Delaisse, 1995; Bord et al., 1998; Engsig et al., 2000; Hou et al., 2004; Inada et al., 2004; Karsdal et al., 2004; Holmbeck et al., 2005; Kasper et al., 2007; Manduca et al., 2009; Lu et al., 2010; Ortega et al., 2010; Tang et al., 2012; Madsen et al., 2013; Lozito et al., 2014; Almalki and Agrawal, 2016 | ||
| Regulate the bioavailability of soluble RANKL, thereby promoting the formation of multinucleated osteoclast cells, acquisition of osteoclast-specific differentiation markers, binding of osteoclasts to bone surfaces, promotion of osteoclast survival, and stimulation of bone resorption. | Bellido et al., 2019 | ||
| Mesenchymal stem cells | Network of multiple MMPs, tissue inhibitors of MMPs and RECK | (i) Modulates the commitment and differentiation of mesenchymal stem cells. (ii) Impacts osteoblastic migration, spreading, and differentiation. |
Kasper et al., 2007; Lu et al., 2010; Lozito and Tuan, 2011; Egea et al., 2012; Almalki and Agrawal, 2016; Mahl et al., 2016 |
| MMP-16 | Controls mesenchymal stem cells viability. | Paiva and Granjeiro, 2017 | |
| MMP-2 and MMP-9 | Promote the directional migration of bone marrow mesenchymal stem cells. | Lv et al., 2017 | |
| Osteocytes | MMP-2, MMP-13 and MMP-14 | Modulate the formation of the osteocyte canalicular network. | Barthelemi et al., 2012 |
| MMP-13 | Regulates the remodeling of the osteocyte lacunar-canalicular network in mid-cortical bone matrix, which is critical for the active maintenance of bone quality (matrix composition, organization, fracture resistance). | Tang et al., 2012; Alliston, 2014 | |
| MMP-14 | Essential for cell adhesion, invasion, and cell-cell communication events. | Hughes et al., 1994; Paiva and Granjeiro, 2017 | |
| Osteoclasts | MMP-9 | Participates in cell recruitment (by generating collagen-derived endostatin which prevents osteoclast chemotaxis), survival (e.g., by activating pro-TNF-α), adhesion (e.g., by cleaving intercellular adhesion molecule-1), as well as in degradation of cytokines important to osteoclastogenesis such as IL-1β. | Gearing et al., 1995; Ito et al., 1996; Ferreras et al., 2000; Fiore et al., 2002 |
| MMP-12 | Modulates the interaction between osteoclasts and bone matrix through multiple mechanisms including: (i) cleavage of osteopontin, vitronectin, bone sialoprotein and osteonectin, (ii) activation of TNF-α, (iii) generation of endostatin from collagen, and (iv) digestion of urokinase-type plasminogen activator receptor/uPAR. | Koolwijk et al., 2001; Hou et al., 2004; Paiva and Granjeiro, 2017 | |
| MMP-14 | Sheds CD14 receptor to impinge on osteoclast adhesion and migration as well as being involved in monocyte/macrophage fusion (e.g., by modulating the Rac1 pathway). | Kajita et al., 2001; Vivinus-Nebot et al., 2004; Gonzalo et al., 2010 | |
| The CD44/MMP-9/MMP-14 axis | Mediates pro-MMP-9 activation on the osteoclast membrane thereby modulating osteoclast migration in bone tissue resorption. | Chellaiah and Ma, 2013 | |
| MMP-14 and MMP-7 | Promote RANKL availability, which implicates the RANK/RANKL/osteoprotegerin axis in osteoclast maturation and activation. | Lynch et al., 2005; Hikita et al., 2006; Aiken and Khokha, 2010 | |
| Bone matrix | MMP-1, -2, -8, -9, -13, -14, and -15 | Necessary for extracellular matrix turnover. | Paiva and Granjeiro, 2017 |
| MMPs -2, -3, -7, -9, -12, -14 | Cleave and regulate bone matrix-associated non-collagenous proteins (such as osteonectin, vitronectin, osteopontin, bone sialoprotein) as well as cell membrane- and matrix-anchored latent growth factors. | Sasaki et al., 1997; Agnihotri et al., 2001; Sage et al., 2003; Lindsey et al., 2015 | |
| MMP-14 | The collagen fragments produced by MMP-14 are endocytosed via uPARAP/Endo180 for total lysosomal degradation. | Lafleur et al., 2006; Lee et al., 2006; Messaritou et al., 2009 | |
| Osteoblasts | MMP-2 | Critical for osteoblast differentiation and survival. | Paiva and Granjeiro, 2017 |
| MMP-14 | Serves to preserve osteoblast survival once osteoblasts have stopped the synthesis of new bone matrix, thus aiding in the transition from osteoblasts to osteocytes. | Karsdal et al., 2004 | |
| Bone remodeling | MMPs from osteoblasts and bone lining cells | Preceding osteoclast adhesion and resorption, MMPs participate in the cleavage of organic matrix (such as cathepsin-cleaved collagen and non-collagenous proteins). | Holliday et al., 1997; Stahle-Backdahl et al., 1997; Yamagiwa et al., 1999; Paiva and Granjeiro, 2017 |
| MMP-13 | Active in regulating bone mass through osteoblasts, and forming osteocyte canalicular network. | Page-McCaw et al., 2007; Barthelemi et al., 2012 | |
| MMP-14/CD44 | Activates Pro-MMP-9 on osteoclast membrane surface during osteoclast recruitment, adhesion, resorption and migration. | Paiva and Granjeiro, 2017 |
MMPs, matrix metalloproteinases; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; TNF, tumor necrosis factor; IL, interleukin; Rac1, Ras-related C3 botulinum toxin substrate 1 pathway; RANK, receptor activator of nuclear factor kappa B; RANKL, RANK ligand; uPARAP/Endo180, endocytic collagen receptor of collagen and collagen fragments for degradation in the lysosomes.