Eugenio Hardy
Carlos Fernandez-Patron- 1Center of Molecular Immunology, Havana, Cuba
- 2Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a general overview of bone’s main players (bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts) that participate in bone remodeling. Placing emphasis on the family of extracellular matrix metalloproteinases (MMPs), we describe how: (i) Convergence of multiple protease families (including MMPs and cysteine proteinases) ensures complexity and robustness of the bone remodeling process, (ii) Enzymatic activity of MMPs affects bone physiology at the molecular and cellular levels and (iii) Either overexpression or deficiency/insufficiency of individual MMPs impairs healthy bone remodeling and systemic metabolism. Today, it is generally accepted that proteolytic activity is required for the degradation of bone tissue in osteoarthritis and osteoporosis. However, it is increasingly evident that inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. We argue that there remains a need to rethink the role played by proteases in bone physiology and pathology.
Introduction
Bone is a hard, dense, rigid form of highly specialized connective tissue making up the skeleton of vertebrates. Bone protects internal organs, supports body structures, and aids in locomotion (Maffioli and Derosa, 2015). In addition, bone provides an environment for hematopoiesis (i.e., formation and development of blood cells) in the bone marrow, and acts as a homeostatic reservoir of calcium, phosphorus, insulin-like growth factors, transforming growth factor-β, and cytokines. Bone buffers the blood against drastic pH changes, thus detoxifying the circulation from heavy metals (Rauner et al., 2012). Bone develops by intramembranous ossification (e.g., bone of the clavicle, some skull bones), endochondral ossification (e.g., the appendicular and axial skeleton) or pseudo-metamorphic ossification (Rauner et al., 2012).
Bone remodeling is a complex process involving the sequential resorption of bone tissue and deposition of new bone at the same site (Kerschan-Schindl and Ebenbichler, 2012). Together with bone structure, geometry, size, and density, remodeling determines bone’s overall mechanical properties (e.g., the strength) (Mosekilde et al., 1993; Jiang et al., 1997; Ikeda et al., 2003; Shahnazari et al., 2009) as well as enables the repair of damaged bone and the adaption of bone to changing biomechanical forces (Kerschan-Schindl and Ebenbichler, 2012).
We review here the prevailing view of the bone remodeling process with an emphasis on well-accepted and newly emerging roles played by matrix metalloproteinases (MMPs) and cysteine proteinases in this process. Finally, we review the increasing number of instances in which inactivating mutations in MMP genes are found to lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth.
General Overview on the Cycle of Bone Remodeling
The bone remodeling process consists of four distinct consecutive phases spanning over 3–6 months (Datta et al., 2008).
The first phase of bone remodeling is known as the ‘activation phase’ and can be triggered by mechanical and nutritional stress on the bone as well as by hormones (e.g., parathyroid hormone, estrogen) (Parra-Torres et al., 2013). As described in Table 1, terminally differentiated osteocyte cell is a key player in the activation phase (Rauner et al., 2012; Parra-Torres et al., 2013).
Table 1. Osteocytes and the activation phase of bone remodeling.
The second phase lasts 8–10 days (Teitelbaum, 2007) and is called the ‘bone resorption phase’ – a process by which large multinucleated osteoclast cells break down old bone organic matrix impregnated with minerals (e.g., calcium phosphate nanocrystals), as described in Table 2.
Table 2. Osteoclasts and the bone resorption phase.
The third ‘reversal’ phase connects osteoclastic bone tissue resorption and osteoblastic bone tissue formation (Delaisse, 2014) and lasts 7–14 days (Pettit et al., 2008; Hienz et al., 2015). After departure of the osteoclast from a cavity in bones undergoing resorption, which is a resorptive lacuna known as the Howship’s lacuna, bone lining cells occupy the Howship’s lacuna and clean it (Everts et al., 2002). The cleaning process occurs by enwrapping and digesting non-mineralized collagenous proteins protruding from the bone surface left by osteoclasts. This cleaning process is a requirement for the subsequent deposition of a first layer of collagen along the Howship’s lacuna (Everts et al., 2002). Four types of osteoclast-derived coupling factors stimulate bone formation during the reversal phase: (i) Matrix-derived factors including transforming growth factor-β, bone morphogenetic protein-2, platelet-derived growth factor, and insulin-like growth factors, which are released during bone tissue resorption, (ii) Osteoclast-secreted factors, including cardiotrophin-1, sphingosine-1-phosphate, collagen triple helix repeat containing 1, and complement factor 3a, (iii) Osteoclast membrane-bound factors such as EphrinB2 and Semaphorin D, and (iv) Structural changes brought about by the osteoclast on the bone tissue surface (Sims and Martin, 2014). Reversal cells originating from pre-osteoblast cells (Andersen et al., 2013) colonize the osteoclast-eroded surface and respond to osteoclast-derived messages and coupling factors along with fibroblast-like cells covering the surface of bone (known as bone lining cells), osteoblast precursors, and canopy cells (Delaisse, 2014; Sims and Martin, 2014; Lassen et al., 2017; Pirapaharan et al., 2019).
The fourth phase of the bone remodeling cycle is ‘formation,’ when mononucleate osteoblast cells synthesize new bone organic matrix formed by collagen fibers and non-collagenous proteins (e.g., bone sialoprotein, osteopontin, osteocalcin, proteoglycans) that later becomes surrounded and impregnated with mineral deposit mainly in the form of calcium hydroxyapatite. A summary of osteoblastogenesis, the roles played by osteoblasts during this last phase, and the fate of osteoblasts is described in Table 3.
Table 3. Osteoblasts and the bone formation phase.
While bone formation surpasses resorption during childhood, bone formation and resorption are in balance during young adulthood. However, an unbalanced bone loss occurs with aging (Datta et al., 2008; Rauner et al., 2012; Brandi and Piscitelli, 2013) and could predispose an individual to skeletal disorders including: (i) inflammatory bone loss in periodontal disease, (ii) arthritis (stimulation of bone resorption and inhibition of bone formation by prostaglandins and cytokines), (iii) osteoporosis (bone resorption outpaces bone formation), (iv) hyperparathyroidism and hyperthyroidism (greatly increased rate of bone resorption and formation), (v) Paget’s disease (increased and abnormal [shape, weakness, and brittleness] bone formation), (vi) osteomalacia (delayed/defficient bone mineralization), and (vi) osteopetrosis (failure of osteoclasts to resorb bone) (Roodman et al., 1992; Delmas, 1995; Gallagher, 1997; Mills and Frausto, 1997; Raisz, 1997; Charles and Key, 1998; Schneider et al., 1998; Siris, 1998; Kini and Nandeesh, 2012).
Matrix Metalloproteinases: Modulators of Bone Remodeling
Matrix metalloproteinases are a family of at least 24 highly homologous, multi-domain enzymes (Figure 1) with the capacity to degrade virtually all extracellular matrix components including collagen, aggrecan, elastin, and fibronectin (Lu et al., 2011; Fernandez-Patron et al., 2016).
Figure 1. Schematic structure and classification of matrix metalloproteinases. S, amino-terminal signal sequence; Pro, pro-peptide; Zn(II)-binding site; h, hinge region; Hpx, hemopexin; FN, collagen-binding type II repeats of fibronectin; F, furin; MT-MMPs, membrane-type MMPs; N, N-terminus; C, C- terminus. MMPs -11, -21, and -28 (all in red) contain a Furin-like cleavage domain. MMPs -17 and -25 (both in green) contain a glycophosphatidyl inositol-anchoring sequence. MMPs -14, -15, -16, and -24 (all in blue) comprise a transmembrane domain with a cytosolic tail. MMP23A and MMP23B lack the signal peptide, the cysteine-switch motif and the hemopexin-like domain, but they contain a unique cysteine-rich domain, an immunoglobulin-like domain and an N-terminal type II transmembrane domain (Velasco et al., 1999).
All MMP family members are synthesized as catalytically inactive (latent) pro-enzymes (pro-MMPs) that contain a: signal N-terminal peptide sequence (∼20 amino acids), pro-peptide domain (∼80 amino acids), catalytic domain (approximately 160 amino acids), hinge (linker peptide) region of variable length (10–30 amino acids), and a hemopexin-like C-terminal domain (Hpx) (∼210 amino acids). The smallest MMPs (MMP-7 and MMP-26) lack the hinge and hemopexin domains, and therefore exhibit a reduced affinity for gelatin. MMP-23 has unique domains (such as the cysteine array, IgG-like domain, interleukin-1 type II receptor-like domains) instead of the hemopexin domain (Massova et al., 1998; Pei et al., 2000; Bode and Maskos, 2003; Visse and Nagase, 2003; Nagase et al., 2006; Piccard et al., 2007; Lopez-Otin et al., 2009; Bonnans et al., 2014; Vandooren et al., 2014; Vandenbroucke and Libert, 2014; Cui et al., 2017). The amino-terminal signal peptide targets the pro-MMPs to the rough endoplasmic reticulum, whereas the C-terminus harbors a cysteine residue and a furin cleavage site (PRCGXPD), both of which are important for conversion into the mature, active enzyme (Bonnans et al., 2014). Presence of an intact pro-peptide accounts for the latency of pro-MMPs, which can be overriden through the activation of a “cysteine-switch” mechanism (Van Wart and Birkedal-Hansen, 1990). The pro-peptide contains a cysteine residue that prevents catalytic activity when it is coordinated with a Zn(II)-ion in the catalytic domain (Springman et al., 1990; Van Wart and Birkedal-Hansen, 1990). The cysteine-Zn(II) interaction can be disrupted by alkylating compounds such as the organomercurial 4-aminophenylmercuric acetate as well as by serine proteases and other MMPs such as membrane-type MMPs, which act at the cell surface to which they anchor through their transmembrane domain/short cytoplasmic tail or by glycosylphosphatidylinositol linkage (Bonnans et al., 2014). MMP autolysis is another mechanism of activation mediated by allosteric perturbation of the inactive proenzyme (Springman et al., 1990; Van Wart and Birkedal-Hansen, 1990; Pei and Weiss, 1995; Pei et al., 2000; Meng et al., 2016). The catalytic domain harbors the Zn(II)-binding motif HEXXHXXGXXH, a catalytic Zn(II), a structural Zn(II), specific pockets related to specificity (S1, S2,…Sn and S1′, S2′,…Sn′) and coordinated Ca(II) ions which confer stabilization. The catalytic Zn(II) is coordinated by three histidine residues (Bode and Maskos, 2003; Bonnans et al., 2014; Vandenbroucke and Libert, 2014). The hinge domain is flexible and mediates interactions with substrates, cell-surface proteins, and tissue inhibitors (Cui et al., 2017; Liu and Khalil, 2017). The hemopexin domain modulates substrate recognition and specificity, binding to cell-surface receptors and inhibitors, activation of MMPs, and cellular MMP internalization for degradation (Visse and Nagase, 2003; Nagase et al., 2006; Piccard et al., 2007).
Matrix metalloproteinases expression and activity are tightly regulated at various levels: gene transcription, translation and secretion of the inactive enzyme precursor, proteolytic activation of the zymogen, spatial localization, interaction with specific extracellular matrix proteins, and inhibition by endogenous inhibitors (such as tissue inhibitors of MMPs [TIMPs 1-4], α2-macroglobulin, and human fibrinogen) (Sottrup-Jensen, 1989; Overall et al., 1991; Kusano et al., 1998; Zeng et al., 1998; Sternlicht and Werb, 2001; Han et al., 2003; Greenlee et al., 2007; Clark et al., 2008; Fanjul-Fernandez et al., 2010; Hadler-Olsen et al., 2011; Arpino et al., 2015; Sarker et al., 2019). Despite their similar names, TIMPs 1-4 exhibit large differences in their primary sequence, tissue expression, transcriptional regulation and in their inhibitory spectrum (Brew et al., 2000). In bone, TIMP-2 and TIMP-3, unlike TIMP-1, are effective inhibitors of the membrane-type MMPs (e.g., MMP-14), while TIMP-3 displays the broadest inhibitory actions of all TIMPs against metalloproteinases. Unlike TIMP-1, -2, and -4, which are soluble, TIMP-3 has basic amino acid residues in its C- and N-termini through which TIMP-3 attaches to heparan and chondroitin sulfate in the extracellular matrix and inhibits both MMPs and members of ‘a disintegrin and metalloproteinase’ (ADAM) and ‘a disintegrin and metalloproteinase with thrombospondin domains’ (ADAMTS) family including ADAM-17 and ADAMTS-4/-5 (Porter et al., 2005; Javaheri et al., 2016). Deficiency of tissue inhibitors (TIMP-1, -2, or -4) has minor impact on bone phenotype. However, both Timp3 deficiency and transgenic overexpression alters craniofacial bones of endochondral and intramembranous origins in mice, while the growth plates appear normal in these mice (Javaheri et al., 2016). Paradoxically, mice deficient in RECK (an MMP inhibitor anchored on the cell membrane with inhibitory actions against MMP-2, -9, and -14 and ADAM-10) die in utero displaying a perturbed extracellular matrix organization (Javaheri et al., 2016).
These observations suggest that bone remodeling may not be solely defined by the balance/imbalance between MMPs and TIMPs. Rather, other molecules expressed and released in the settings of bone physiology and pathology such as RECK (Paiva and Granjeiro, 2014) and some acute phase reactants (alpha 2-macroglobulin, fibrinogen) may regulate/dysregulate MMP activity in inflammatory conditions thus perturbing the normal bone remodeling process (Cook et al., 2018; Sarker et al., 2019). A consequence implied by the latter notion is that MMPs, ADAMs and ADAMTS molecules may be released from bone or non-bone tissues to influence bone remodeling through autocrine and paracrine actions. In other words, MMPs likely circulate bound to non-classical inhibitors (such as acute phase reactants) being recruited to sites of active bone remodeling, where local substrates act as chemoattractants and local activators (other proteases, reactive oxygen species) activate them.
The aforementioned levels of regulation effectively dissociate MMP expression from MMP activity (e.g., since overexpression of endogenous MMP inhibitors would effectively reduce MMP activity). Current biochemical techniques for assessing MMP activity are non-reliable. However, as research requires a proxy, MMP expression is often used as a surrogate (albeit incorrectly) for MMP activity. There remains an urgent need for highly sensitive, specific, and robust methods for assessing the activity potential of individual MMPs such that therapeutic strategies can be designed to specifically reduce the activity of overactive MMPs (i.e., those whose activity levels are above baseline) or to increase the activity of underactive MMPs (i.e., those whose activity levels are below baseline).
Roles of MMPs Associated to Bone Development and Remodeling
The biochemical actions of MMPs are intimately linked to their cells of origin. Table 4 describes cell-specific roles of MMPs in physiological bone remodeling. Osteoclast-mediated bone resorption in calvaria and long bones requires normal enzymatic activity of MMPs and cysteine proteinases such as cathepsin K whose deficiency impairs bone remodeling (Everts et al., 1999; Delaisse et al., 2003). This is evidenced in osteoclasts from patients with pycnodysostosis (an osteopetrosis-like bone disease related to loss-of-function mutations in the cathepsin K gene) and osteoclasts from cathepsin K-deficient mice which are unable to efficiently digest organic bone matrix, resulting in large, mineral-free areas of bone matrix (Everts et al., 1998, 2009). Cysteine proteinases synthesized and used by the different osteoclasts for bone matrix digestion (Everts et al., 2006) can degrade intramembranous bones as well as osteoclast-derived MMPs (Everts et al., 2009). Cysteine proteinases are secreted to act in the low pH environments formed by osteoclasts in the resorption sites, with MMPs degrading the rest of the bone matrix when the pH increases (Everts et al., 1998) as well as contributing to the digestion of fibrillar, non-mineralized collagen in Howship’s lacunae abandoned by osteoclast cells (Everts et al., 2002). These complementary and overlapping contributions of the MMP and cysteine proteinase families make the process of bone tissue remodeling both complex and robust.
Table 4. Specific roles of MMPs under physiological conditions in bone remodeling.
The involvement of MMPs in bone remodeling has become clear with the aid of animal models such as MMP-deficient mice, which show a variety of bone abnormalities (Table 5). Impaired bone tissue remodeling in Mmp2–/– mice (Table 5, row 2) is characterized by a reduced number of osteoblasts and osteoclasts, disruption of the canicular network exacerbating osteocyte death, disruption of the MMP-2-osteopontin-bone sialoprotein axis, and promotion of osteolysis (Martignetti et al., 2001; Inoue et al., 2006; Mosig et al., 2007; Malaponte et al., 2016). MMP-9-deficient mice show alterations in cartilage-bone replacement during endochondral ossification (Vu et al., 1998) (Table 5, row 3). This phenotype may be explained by an inefficient degradation of the cartilage matrix, which leads to a diminished bioavailability of extracellular matrix-derived vascular endothelial growth factor and consequently effects osteoclasts and endothelial cells movement into the cartilage (Ortega et al., 2010). Bone tissue modeling and remodeling processes are altered in MMP-13 deficient mice (Table 5, row 4) (Inada et al., 2004; Stickens et al., 2004; Ortega et al., 2005). MMP-14 deficiency (Table 5, row 5), which is associated with high lethality, results in the most drastic skeletal phenotype among MMP-deficient mice (Holmbeck et al., 1999; Zhou et al., 2000). Double gene-deficient mice lacking at least one MMP gene have been engineered and their bone phenotype have been studied. For instance, double-knockout mice lacking MMP-2 and uPARAP/Endo180 (endocytic receptor of collagen and collagen fragments for degradation in the lysosomes) show reduced bone mineral density, short long bones, and poor trabecular bone quality (Madsen et al., 2013). MMP-8 and MMP-13 double-deficient mice have abnormal growth plate as well as augmented metaphyseal trabecular bone mineral density (Inada et al., 2001, 2002; Stickens et al., 2004). Double knockout mice lacking MMP-9 and MMP-13 exhibit expanded growth plates, disorganized hypertrophic chondrocyte zone, increased number of end-differentiated hypertrophic cells, and delayed formation of the bone marrow cavity (Kennedy et al., 2005; Paiva and Granjeiro, 2014). The bone phenotype of mice with a double knockout for MMP-14 and MMP-2 reassembles that of MMP-14-deficient mice (Oh et al., 2004). MMP-14 and MMP-16 double-knockout mice develop a bone phenotype that affects ossification (intramembranous and endochondral) and is characterized by severe irregularities, including (i) high mortality associated to developmental defects, (ii) noticeable craniofacial malformations such as cleft palate, thinner cranial vault bones, deficiently developed parietal, as well as frontal and nasal bones, (iii) altered growth plate, and (iv) cortical bone shortening (Paiva and Granjeiro, 2014). MMP-14 and uPARAP/Endo180 double-knockout mice die soon after birth (Wagenaar-Miller et al., 2007). As listed in Table 6, MMP activity contributes to numerous bone pathologies including arthritis, osteoporosis, osteonecrosis, periodontitis, sinonasal osteitis, degenerated lumbar disk tissues, and bone cancer metastasis (Aiken and Khokha, 2010; Koskinen et al., 2011; Mittal et al., 2016; Rose and Kooyman, 2016; Lazarus et al., 2017; Paiva and Granjeiro, 2017; Tauro and Lynch, 2018; Zhang et al., 2018). The roles played by MMPs in these pathologies are influenced by non-matrix proteins such as TIMPs, transforming growth factor, vascular endothelial growth factor, bone morphogenic proteins, activated protein C, and the Wnt [Wingless-type MMTV integration site family]/β-catenin (Table 7).
Table 5. Selected skeletal phenotypes associated to MMP deficiency in mice.
Table 6. Involvement of MMPs in bone pathologies.
Table 7. Interactions of MMPs with other proteins in bone development/remodeling.
MMPs as Sheddases
Beyond the direct degradation of extracellular matrix substrates (e.g., collagen), MMP-mediated cleavage of substrates can lead to the release (shedding) into the extracellular matrix of soluble fragments of cell membrane-anchored receptor ligands. This extracellular event enables ligand-mediated activation of cognate receptors and elicits downstream intracellular signal transduction cascades which modify gene transcription and, ultimately, cell behavior. A prominent example pertinent to osteoblasts is the release of RANKL, which is the ligand of receptor activator of nuclear factor kappa B (RANK), by MMP-14. This MMP-14/RANKL/RANK/signal transduction axis regulates osteoblastogenesis and osteoclastogenesis, making MMP-14 crucial for normal bone formation (Bonfil et al., 2007; Thiolloy et al., 2009; Sabbota et al., 2010; Bonfil and Cher, 2011). The ligand shedding activity of MMPs influences the propensity to cancer metastasis and bone disease. For instance, MMP-14-mediated shedding of RANKL and downstream activation of RANK in the left supraclavicular lymph node cells of the prostate stimulates the non-receptor tyrosine kinase, SRC, to effectively increase the migration of prostate tumor cells which can metastasize to bone (Sabbota et al., 2010). Similarly, osteoclast-derived MMP-7 solubilizes osteoblast-bound RANKL whose release into the tumor-bone microenvironment promotes osteoclast activation in bone metastatic sites contributing to prostate and mammary tumor-induced osteolysis (Lynch et al., 2005; Thiolloy et al., 2009).
MMP-Generated Neoepitopes
The proteolytic action of MMPs on extracellular matrix macromolecules can result in the exposure of neo-epitopes (i.e., unique bioactive MMP-generated fragments). Compared to healthy subject controls, patients with ankylosing spondylitis (which is a form of arthritis that causes inflammation of the vertebrae) show significantly higher levels of different neo-epitopes such as C1M, C2M, C3M, C4M, C5M, C6M, and C7M from collagen type I, II, III, IV, V, VI, and VII (Veidal et al., 2012; Genovese and Karsdal, 2016). Some of these neo-epitopes have been combined (e.g., C2M, C3M, and C6M) for diagnostic purposes (Bay-Jensen et al., 2012). IPEN341-342FFGV is an MMP cleavage site which could be useful as diagnostic and prognostic makers for osteoarthritis (Bay-Jensen et al., 2011). Similarly, other MMP-generated neo-epitopes derived from collagen type II (e.g., C2C, C2M, C-terminal telopeptide of type II collagen (CTX-II), and TIINE) hold biomarker potential for osteoarthritis (Karsdal et al., 2010; Qvist et al., 2010; Karsdal et al., 2011).
Over-Overexpression of MMPs
Over-expression of MMPs is frequently reported in arthritis (Burrage et al., 2006; Tokito and Jougasaki, 2016). Collagenolytic MMPs (such as MMP-1, -2, -8, -13, and -14) are expressed in the arthritic joint and likely participate in the degradation of cartilage type II collagen, while MMP-3, -7, and -9 can degrade aggrecan leading to joint destruction (Puliti et al., 2012; Tokito and Jougasaki, 2016). Such a pathological mechanism has been proposed for MMP-3 and MMP-13 in degenerative joint disease in the elderly (Neuhold et al., 2001; Troeberg and Nagase, 2012; Jackson et al., 2014; Pap and Korb-Pap, 2015). Other contributions to osteoarthritis from activities related to MMP-3 include MMP-3-mediated activation of MMP-1 and MMP-13 (Mancini and di Battista, 2006; Tokito and Jougasaki, 2016). In rheumatoid arthritis, MMP-14 is greatly expressed in fibroblast-like synoviocytes and macrophages, and it could be an effector to cartilage destruction (Pap et al., 2000; Sabeh et al., 2010). MMP-1 and MMP-3 likely participate in cartilage destruction in rheumatoid arthritis and osteoarthritis (Burrage et al., 2006; Fiedorczyk et al., 2006; Tokito and Jougasaki, 2016). As a result, MMP overexpression could be therapeutically targeted in arthritis (Tokito and Jougasaki, 2016). Whether reducing MMP expression (or activity) levels provides a clinical benefit is unclear. In experimental models, many synthetic MMP inhibitors have shown positive effects (Ishikawa et al., 2005). At the clinical level, however, all efforts with MMP inhibitors to block the damaging activity of MMPs in arthritis and other non-neoplastic conditions were regrettably unsuccessful (Burrage et al., 2006; Tokito and Jougasaki, 2016). Reasons for these failures include: (i) deficient clinical trial designs (Burrage et al., 2006), (ii) unwanted characteristics of MMP inhibitors (side effects including musculoskeletal pain, low oral bioavailability, short in vivo half-lives, and lack of selectivity [Iyer et al., 2012; Fields, 2015; Tokito and Jougasaki, 2016]), (iii) inability of MMP inhibitors to infiltrate the cartilage/bone/synovial interface (Burrage et al., 2006), (iv) neglect of the highly complex functions served by MMPs in physiological and disease states (Iyer et al., 2012; Li et al., 2013; Sawicki, 2013) and (v) broad tissue distribution and substrate promiscuity exhibited by MMPs and their substrates (Burrage et al., 2006; Tokito and Jougasaki, 2016). To date, there remains a need for highly selective MMP inhibitors and for better information on the disease-specific substrates, which could be therapeutically targeted as shown by recent studies with MMP-13 in osteoarthritis (Li et al., 2011) as well as for more efficient and reliable techniques to sensitively measure condition-specific MMP activity potential (not just MMP expression levels).
MMP Gene Polymorphism
A nucleotide polymorphism, by which an additional guanine creates an ETS transcription factor binding site (5′-GGA-3′) at position 1607 in the promoter sequence of the MMP-1 gene, has been related to bone mineral density (BMD) (Rutter et al., 1998). This polymorphism is associated with increased transcription of the MMP-1 gene and elevated MMP-1 activity. Among 819 postmenopausal Japanese women, BMD (e.g., D50, D100) for the distal radius had a lower value in women with the GG/GG genotype (47.9%) than in those with other (e.g., G/GG [41.9%], G/G [10.3%], G/G + G/GG [52.1%]) genotypes. A -1562C3 thymine polymorphism in the MMP-9 gene has been related to BMD in a population-based study (1114 Japanese men and 1087 women). It seems that the T allele (e.g., in men with CT or TT genotypes) of MMP-9, which shows greater transcriptional activity than the C allele (e.g., in men with CC genotype), is linked to decreased bone mass, and has a predominant effect on BMD (Zhang et al., 1999; Yamada et al., 2004). A single nucleotide polymorphism rs17576 may be involved in the pathogenesis of lumbar disk herniation (Jing et al., 2018); while the G allele of rs17576 appears to correlate with more severe stages of disk degeneration.
MMP Deficiency and Insufficiency in Humans
Having discussed the roles of MMPs under physiological and pathological conditions, we will next discuss how their deficiency and insufficiency relates to bone metabolic abnormalities.
MMP-2 gene deficiency leads to a rare human skeletal disorder1, which was first reported in consanguineous Saudi Arabian families, and is characterized by severe bone alterations (Martignetti et al., 2001). Osteolytic and metabolic changes linked to MMP-2 deficiency affect tarsal, carpal, and phalangeal bones, cause severe arthropathy, osteoporosis, fibrous nodules, distinctive craniofacial defects such as exophthalmos, brachycephaly, and flattened nasal bridges and dwarfism (Al-Aqeel et al., 2000; Al-Mayouf et al., 2000; Al-Aqeel, 2005; Mosig et al., 2007; Page-McCaw et al., 2007; Castberg et al., 2013). This complex syndrome is currently categorized as a form of Torg syndrome and results from homoallelic mutations in the gene for MMP-2 located at 16q12-21 (Martignetti et al., 2001; Liang et al., 2016). A Tyr codon in the MMP-2 prodomain is replaced with the Y244X stop codon and an Arg is replaced with a His (R101H) in the cysteine-containing domain (PRCGNPD substituted by PHCGNPD). The R101H mutation is suggested to perturb coordination of Cys102 to the catalytic Zn(II) domain, consequently activating intracellular pro-MMP-2 and leading to its auto-degradation (Kennedy et al., 2005; Krane and Inada, 2008). A homoallelic missense mutation in the catalytic Zn(II) domain (E404K) has been revealed in Winchester syndrome (another variant of multicentric osteolysis) (Zankl et al., 2005). These rare Torg and Winchester arthritic syndromes together with others (such as multicentric osteolysis with nodulosis and arthropathy [known as MONA]) belong to a general family of hereditary autosomal dominant and recessive skeletal disorders with progressive bone loss and joint destruction (Al-Mayouf et al., 2000; Martignetti et al., 2001; Al-Aqeel, 2005; Zankl et al., 2005; Rouzier et al., 2006; Mosig et al., 2007; Tuysuz et al., 2009).
Similar to MMP-2, a homozygous dominant mutation (Ser substituted by Phe [F56S]) in the pro-region domain of MMP-13 also results in a bone development disorder known as spondyloepimetaphyseal dysplasia-Missouri type (Kennedy et al., 2005)2. This disorder, which appears to spontaneously resolve by adolescence, is characterized by anomalous modeling of long bones, mild defects in epiphysis, moderate to severe changes in the metaphysis morphology, pear-shaped vertebrae, femoral and tibial bowing, genu varum deformities, and osteoarthritis. While the biochemical mechanisms linking MMP-13 to these bone abnormalities remain unclear, the phenotype of MMP-13 deficiency could be due to a late exit of chondrocyte cells from the growth plate (Kennedy et al., 2005).
MMP-14 is widely considered one of the physiological activators of MMP-2 as it converts pro-MMP-2 into mature MMP-2 at the cell surface (Fernandez-Patron et al., 2016). An MMP-14 homoallelic mutation (T > R replacement in the signal peptide domain) destabilizes the interaction (e.g., recognition and binding) of the MMP-14 signal peptide with the signal recognition particle complex, thus affecting MMP-14 targeting to the plasma membrane (Evans et al., 2012). This MMP-14 homoallelic mutation causes an apparent deficiency of biochemically active MMP-14 at the cell membrane which impairs pro-MMP-2 activation and causes a condition of MMP-2 activity deficiency with Winchester syndrome (Evans et al., 2012)3.
A missense homozygous mutation (g.16250T > A, which replaces His226 of the Zn(II) catalytic domain with Gln [p.H226Q]), in the MMP20 gene disrupts the metal-binding site and prevents MMP-20 proteolytic activity regarding enamel matrix proteins (Ozdemir et al., 2005)4. This mutation may lead to autosomal-recessive hypomaturation amelogenesis imperfecta, a group of inherited heterogeneous diseases that alter enamel development (amount, composition, structure) in humans (Kim J.W. et al., 2005). Another mutation in the intron 6 splice acceptor (g.30561A > T) that causes this disease is specifically characterized by pigmented teeth with a mottled and rough surface (Kim J.W. et al., 2005).
Partial loss of MMP activity or impaired MMP secretion can lead to MMP activity insufficiency. A pervasive cause of MMP insufficiency can be medications with such MMP inhibitory actions including: (i) Statins (200 million prescriptions in the United States/year; 14 million prescriptions for lovastatin alone in 2014)5 which can cause myositis and rhabdomyolysis (Luan et al., 2003; Thompson et al., 2003). (ii) Doxycycline (7 million prescriptions in 2014)5 with side-effects including joint inflammation in humans and cardiac inflammation in mice (Berry et al., 2015). (iii) Therapeutic antibodies against MMPs and MMP inhibitor drugs for treating patients with rheumatoid arthritis, severely active Crohn’s disease, and cystic fibrosis6. If these antibodies reduce MMP activity below baseline levels, they would cause MMP insufficiency with unpredictable consequences. Pharmacological MMP-inhibitors in Phase 3 clinical trials conducted during 1997 and 1998 in patients with advanced cancers led to an as of yet poorly understood, very severe inflammatory musculoskeletal syndrome (Zucker et al., 2000; Coussens et al., 2002). Another common cause of MMP insufficiency could be the pathological elevation of endogenous MMP inhibitors (e.g., tissue inhibitors of MMPs, α-2-macroglobulin, RECK) (Mott et al., 2000; Oh et al., 2001; Nagase et al., 2006; Klein and Bischoff, 2011). In addition, there is fibrinogen, an acute phase reactant in arthritis, which our laboratory discovered recently to inhibit MMP-2 in a cohort of rheumatoid arthritis patients (Sarker et al., 2019).
Summary
In summary, bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts are responsible for constant bone tissue remodeling (Figure 2). The activation of this multicellular unit and the intense communication between the bone cells is tightly regulated by mechanical stimuli, apoptosis, as well as systemic and local factors such as hormones and cytokines including RANKL, CSF-M, IL-3, and IL-6. Proteases of the MMP and cysteine proteinase families converge in the modulation of bone remodeling. Whereas proteolytic activity has long been thought to be required for the degradation of bone tissue in osteoarthritis and osteoporosis, inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. Thus, there remains a need to rethink the role played by proteases in bone physiology and pathology. More specific information related to bone remodeling and presumed pathways by which proteases, in particular MMPs, contribute to bone tissue remodeling in health and disease is provided in previous excellent reviews (Kini and Nandeesh, 2012; Rauner et al., 2012; Hienz et al., 2015; Liang et al., 2016; Mittal et al., 2016; Franco et al., 2017; Paiva and Granjeiro, 2017; Tauro and Lynch, 2018; Plotkin and Bruzzaniti, 2019).
Figure 2. Schematic representation of the bone remodeling cycle with emphasis on the manifold roles played by matrix metalloproteinases. (A) Osteocytes detect mechanical stress or respond to biochemical stimuli. (B) Lining cells of the endosteal bone surface retract and proteases (e.g., MMPs) remove bone underlying membrane. (C) Osteoclasts are attracted and fused to become activated. (D) The underlying bone is digested by active multinucleated osteoclasts. (E) Osteoblasts are recruited to the bone resorption cavity. (F) New osteoid is formed by osteoblasts, and then mineralized (Datta et al., 2008; Fernandez-Patron et al., 2016; Paiva and Granjeiro, 2017; Cook et al., 2018). Other pathologies related to inactive/underactive MMPs are excessive inflammation, cardiovascular disorders, and metabolic dysregulation. MMP underactivity could also result from undesired side effects of common medications with MMP inhibitory actions (e.g., statins) (Cook et al., 2018). MSCs, mesenchymal stem cells; GFs, growth factors; RUNX2, runt-related transcription factor 2; RANKL, receptor activator of NF-kappa B ligand.
Author Contributions
EH and CF-P worked together on the conception, design, edition, revision, and approval of review manuscript.
Funding
CF-P was supported by a Natural Sciences and Engineering Research Council of Canada Discovery Grant.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We thank MSc. Angela Sosa for help with Figure 2 illustration.
Footnotes
- ^ https://omim.org/entry/120360
- ^ https://www.omim.org/entry/600108
- ^ https://www.omim.org/entry/600754
- ^ https://www.omim.org/entry/604629
- ^ http://clincalc.com/DrugStats
- ^ http://www.gilead.com
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Keywords: bone, remodeling, metabolism, matrix metalloproteinase, deficiency, underactivity
Citation: Hardy E and Fernandez-Patron C (2020) Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases. Front. Physiol. 11:47. doi: 10.3389/fphys.2020.00047
Received: 24 September 2019; Accepted: 21 January 2020;
Published: 05 February 2020.
Edited by:
Yoshimi Nakagawa, University of Tsukuba, JapanReviewed by:
David M. Findlay, The University of Adelaide, AustraliaVincent Everts, VU University Amsterdam, Netherlands
Copyright © 2020 Hardy and Fernandez-Patron. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Eugenio Hardy, ZXVnZW5pb0BjaW0uc2xkLmN1; Carlos Fernandez-Patron, Y2YyQHVhbGJlcnRhLmNh