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 Table of Contents  
Year : 2016  |  Volume : 2  |  Issue : 1  |  Page : 5-11

Resorptive Cells in Health and Disease

1 Department of Oral Pathology and Microbiology, Bhojia Dental College, Baddi, Solan, Himachal Pradesh, India
2 Department of Prosthodontics, Bhojia Dental College, Baddi, Solan, Himachal Pradesh, India

Date of Web Publication27-Jun-2016

Correspondence Address:
Swati Gautam
Department of Oral Pathology and Microbiology, Bhojia Dental College, Baddi, Solan, Himachal Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2393-8692.184727

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Clastic cells are responsible for the resorption of mineralized matrix of hard tissues. Bone resorbing cells are called osteoclasts; however, they are able to resorb mineralized dental tissues or calcified cartilage, and then, they are called odontoclasts and chondroclasts, respectively. Clastic cells form when mononuclear precursors derived from a monocyte-macrophage cell lineage are attracted to certain mineralized surfaces and subsequently fuse and adhere to them for exerting their resorbing activity. The clastic cells are responsible for degradation of calcified extracellular matrix composed of organic molecules and hydroxyapatite. This process is mainly required in bone turnover and growth, spontaneous and induced (orthodontic) tooth movement, tooth eruption, and bone fracture healing, as well as in pathological conditions, such as osteoporosis, osteoarthritis, and bone metastasis. In addition, they are responsible for daily control of calcium homeostasis. Clastic cells also resorb the primary teeth for shedding before the permanent teeth erupt into the oral cavity.

Keywords: Chondroclasts, hydroxyapatite, odontoclasts, osteoclasts

How to cite this article:
Gautam S, Sharma A, Garg D. Resorptive Cells in Health and Disease. Indian J Oral Health Res 2016;2:5-11

How to cite this URL:
Gautam S, Sharma A, Garg D. Resorptive Cells in Health and Disease. Indian J Oral Health Res [serial online] 2016 [cited 2021 Mar 6];2:5-11. Available from: https://www.ijohr.org/text.asp?2016/2/1/5/184727

  Introduction Top

Bone is not inert tissue but dynamically metabolized connective tissue throughout life. [1] Old bone matrices are always replaced by newly formed matrices. This continual process, named bone remodeling, is important for maintaining bone volume and strength. Bone volume is maintained by the balance of bone resorption and bone formation. Bone cells consist of osteoblast lineage cells and osteoclast-lineage cells. [2] Their differentiation and function are regulated by osteotropic hormones and cytokines. [3]

Bone resorption is necessary for many skeletal processes. It is an obligatory event during bone growth, tooth eruption, and fracture healing and is also necessary for the maintenance of an appropriate level of blood calcium. In the adult human skeleton, continuous physiological remodeling of bone is exclusively dependent on bone resorption. In several human diseases (e.g., malignant hypercalcemia and postmenopausal osteoporosis), enhanced bone resorption is the key pathophysiological event and therapies for these diseases are currently based on its inhibition. In contrast, some rare genetic disorders are manifested as decreased resorption and lead to osteopetrosis. [4] Resorption is a condition associated with either a physiologic or a pathologic process resulting in a loss of dentin, cementum, or bone.

Osteoclasts are cells essential for physiologic remodeling of bone and also play important physiologic and pathologic roles in the dentofacial complex. Osteoclasts and odontoclasts are necessary for tooth eruption yet result in dental compromise when associated with permanent tooth internal or external resorption. [5]

Osteoclasts are multinuclear cells derived from hematopoietic stem cells. [6] Bone resorption is a complex process involving highly coordinated interactions between osteoblasts and osteoclasts that are modulated by receptor activator of nuclear factor kappa-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) system. [6]

This review describes morphological characteristics of resorptive cells and their implication in oral health and disease.

  Key resorptive cells Top

Monocytes and macrophages

Monocytes and macrophages, along with osteoclasts, play an important role in bone and tooth resorption. They are found in tissue sections adjacent to bone resorbing surfaces of rheumatoid arthritis, periodontal disease, periradicular granulomas and cysts, and in metastatic bone tumors. [7] These cells play a critical role in the development and healing of all wounds. Monocytes are recruited to the site of irritation by the release of many proinflammatory cytokines and thus differentiate into macrophages. The migration and recruitment of macrophages are regulated by macrophagic chemotactic factors that are derived from bone and tissue breakdown products and are controlled by increased intracellular levels of adenosine 3,5-cyclic phosphate (cAMP) and calcium. Although macrophages have a structure similar to that of osteoclasts and the osteoclasts can also become multinucleated giant cells, macrophages lack a ruffled border that is attached to hard tissue substrates during resorption and do not create lacunae on the dentinal surface. [8]

  Clastic cells Top

The cells involved in resorption other than monocytes and macrophages are osteoclasts, odontoclasts, dentinoclasts, and cementoclasts. [7] Osteoclasts are multinuclear cells derived from hematopoietic stem cells. Their differentiation pathway is common to that of macrophages and dendritic cells. Thus, a promyeloid precursor can differentiate into either an osteoclast, a macrophage, or a dendritic cell, depending on whether it is exposed to RANKL (also called tumor necrosis factor [TNF]-related activation-induced cytokine, OPG ligand or osteoclast differentiation factor), macrophage colony-stimulating factor (M-CSF), or granulocyte-M-CSF, respectively. [6] Odontoclasts probably have the same origin as osteoclasts. Odontoclasts are derived from tartrate-resistant acid phosphatase (TRAP)-positive circulating monocytes. Odontoclasts are generally smaller in size, having fewer nuclei and form smaller resorption lacunae than the osteoclasts. [9] Prostaglandin E2 (PGE2) may induce cementoclast formation by controlling the balance of RANKL/OPG expression levels in cementoblasts via the EP4-cAMP-protein kinase A (PKA) pathway, in a manner similar to that of parathyroid hormone-related peptide (PTHrP). PGE2 stimulates cementoblast-mediated cementoclast activity in vitro through control of RANKL, interleukin-6 (IL-6), and OPG mRNA and protein in cementoblasts, mainly via the EP4 pathway, similar to the role of PGE2 in osteoblasts. [10]

  Physiology of resorption Top

To maintain stability and integrity of bone, it is constantly undergoing remodeling, with about 10% of bone material being renewed each year. Bone remodeling is a complex process that involves bone resorption performed by osteoclasts, followed by bone formation carried out by osteoblasts. [11] The complex process of bone resorption occurring during both physiologic and pathologic instances involves highly coordinated interaction between osteoblasts and osteoclasts that are modulated by enzymes, hormones, and RANK/RANKL/OPG system. It is suggested that the OPG/RANKL/RANK system is instrumental for interactions between bone, vascular, and immune cells. These protein ligands function as paracrine regulators of osteoclastogenesis and bone metabolism and share homologies with members of the TNF receptor superfamily. [12]

Resorption requires cellular activities: Migration of the osteoclast to the resorption site, its attachment to bone, polarization and formation of new membrane domains, dissolution of hydroxyapatite, degradation of organic matrix, removal of degradation products from the resorption lacuna, and finally either apoptosis of the osteoclasts or their return to the nonresorbing stage. After migration of the osteoclast to a resorption site, a specific membrane domain, the sealing zone, forms under the osteoclast. The plasma membrane attaches tightly to the bone matrix and seals the resorption site from its surroundings. [13]

Integrins play an important role in the early phases of the resorption cycle. At least four different integrins are expressed in osteoclasts: avb3, avb5, a2b1, and avb1. [14]

Resorbing osteoclasts contain not only the sealing zone but also at least three other specialized membrane domains: A ruffled border, a functional secretory domain, and a basolateral membrane. As the osteoclast prepares to resorb bone, it attaches to the bone matrix through the sealing zone and forms another specific membrane domain, the ruffled border. The ruffled border is a resorbing organelle, and it is formed by fusion of intracellular acidic vesicles with the region of plasma membrane facing the bone [Figure 1].
Figure 1: Bone resorption

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The main physiological function of osteoclasts is to degrade mineralized bone matrix. This involves dissolution of crystalline hydroxyapatite and proteolytic cleavage of the organic matrix, which is rich in collagen. Before proteolytic enzymes can reach and degrade collagenous bone matrix, tightly packed hydroxyapatite crystals must be dissolved. It is now generally accepted that the dissolution of mineral occurs by targeted secretion of HCl through the ruffled border into the resorption lacuna. [15] After solubilization of the mineral phase, several proteolytic enzymes degrade the organic bone matrix although the detailed sequence of events at the resorption lacuna is still obscure. Two major classes of proteolytic enzymes, lysosomal cysteine proteinases and matrix metalloproteinases (MMPs) are responsible for matrix degradation. [16] After matrix degradation, the degradation products are removed from the resorption lacuna through a transcytotic vesicular pathway from the ruffled border to the functional secretory domain, where they are liberated into the extracellular space. [17]

The unique structural arrangement of the osteoclasts to hard tissues allows the cell to establish a microenvironment between the ruffled border and the bone, in which resorption takes place. The resorptive process itself can be described as being bimodal, involving the degradation of the inorganic crystal structure of hydroxyapatite and the organic structure of collagen, principally Type 1. The activated osteoclasts produce an acidic pH (3.0-4.5) in their microenvironment. At pH 5 or lower, the solubility of hydroxyapatite increases dramatically and resorption of hard tissue can occur. This acidic environment is primarily achieved through the action of a highly active polarized proton pump contained within the ruffled border. The enzyme carbonic anhydrase II (CA II), which is specific to osteoclasts, also plays a critical role in establishing a subosteoclastic acidic pH. The CA II catalyzes the intracellular conversion of CO 2 to H 2 CO 3 , which provides a readily available source of H + ions to be pumped into the subosteoclastic region. [9]

Odontoclasts are thought to differentiate from circulating progenitor cells such progenitor cells reside in the dental pulp and periodontal ligament (PDL), sharing similar characteristics with osteoclasts such as the expression of cathepsin K, cathepsin D, TRAP, MMPs-9, H + -ATPase, membrane Type 1-MMP expression, and the formation of a clear zone and ruffled border. [5] RANK receptor is expressed by odontoclasts and RANKL by odontoblasts, pulp, and PDL fibroblasts [Figure 2]. [18]
Figure 2: Activation of osteoclast

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  Role of resorptive cells in oral health and diseases Top

Role in physiological root resorption

The resorbing activity of odontoclasts is related to expression of the OPG/RANKL/RANK system by PDL cells. It has been shown that PDL cells, isolated from either nonresorbing deciduous teeth or permanent teeth, express OPG but not RANKL. [19] In the dental follicle environment, the ratio of OPG to RANKL supports, rather than inhibits, osteoclastogenesis. Cytotrophic factors released from the dental follicle and/or the stellate reticulum, such as PTHrP, interleukin-1α, and transforming growth factor-β1, stimulate the expression of RANKL during permanent tooth eruption. Among these factors, PTHrP controls regulation of the relative expression levels of RANKL/OPG on dental follicle cells, as well as in human PDL cells. PTHrP increases RANKL and downregulates OPG expression via a cAMP/PKA protein kinase-independent pathway, consequently leading to physiological root resorption of deciduous teeth and successful eruption of permanent teeth [Figure 3]. [20]
Figure 3: Physiological root resorption

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Role in pathologic root resorption

During orthodontic tooth movement, on the compressed side of the tooth, RANKL expression is induced. [21] RANKL activates osteoclastogenesis, and this is better demonstrated by the acceleration of tooth movement, which is achieved after transfer of the RANKL gene to the periodontal tissue. [22] In contrast, it seems that on the tensile side of an orthodontically moving tooth, there is an increase in OPG synthesis. It has been reported that application of tensile stretching to osteoblasts results in induction of OPG mRNA in PDL cells, and this upregulation of OPG synthesis is reportedly magnitude dependent. Such tensile strain also induces a decrease of RANKL release and RANKL mRNA expression in cultured osteoblasts. The relative expression of OPG and RANKL on the tensioned and the compressed sides of the tooth regulates bone remodeling during orthodontic tooth movement [Figure 4]. [12]
Figure 4: Pathological resorption

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Role in periodontitis

During an inflammatory response, cytokines, chemokines, and other mediators stimulate periosteal osteoblasts, altering the expression levels of RANKL on the osteoblast surface. [23] RANKL is expressed by osteoblasts in the form of a membrane-bound protein or cleaved into a soluble form. [24] IL-1 stimulates osteoclastogenesis and bone resorption, largely through upregulation of RANKL while TNF can stimulate osteoclastogenesis directly or indirectly through RANKL. Inhibition of RANKL caused a decrease in alveolar bone loss in several models of periodontal disease [Figure 5]. [25]
Figure 5: Periodontitis

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Paget's disease

Evidence exists for a genetic predisposition for Paget's disease with a gene locus identification on chromosome 18q-21-22. Most of the evidence centers on the gene factors capable of altering the normal osteoclast behavior. Malfunction of the RANK/RANKL/OPG pathway results in either too much or too little total bone formation. Further, IL-6 plays an important role by increasing the hyper-responsivity of the osteoclast and its precursor cells. Involvement of genes encoding RANK, OPG, VCP, and SQSTM1 in pagetoid diseases provides strong arguments for the role of deregulated NF-kB signaling. This pathway is a key player in osteoclastogenesis that is to a large degree regulated by RANK and OPG. Both SQSTM1and VCP have a role in intracellular NF-kB signaling; the former is a scaffolding protein facilitating NF-kB signaling and the latter participates in proteasomal degradation of IkB, a downstream mediator of NF-kB signaling. [26]


Osteopetrosis is also called "marble bone disease" due to the exaggerated bone density. The osteopetroses can be generally segregated into two clinical forms; the autosomal dominant, adult (benign) type and the autosomal recessive, infantile (malignant) form that is profoundly more severe; however, there are other forms that are associated with other organ systems (Villa et al., 2009). Numerous genes have been identified for their association with compromised osteoclast function. Four genes are most widely linked to human osteopetroses. Generally speaking, the severity of the osteoclast compromise is directly related to the severity of the phenotypic presentation of the condition. [5] The gene for adult osteopetrosis has been mapped to chromosome 1p21. [27] Similar to bisphosphonate-associated osteonecrosis, the pathogenesis of all true forms of osteopetrosis involves diminished osteoclast-mediated skeletal resorption. The number of osteoclasts is often increased; however, as they fail to function normally, bone is not resorbed. This defective osteoclastic bone resorption, along with continued bone formation and endochondral ossification, leads to cortical bone thickening and cancellous bone sclerosis. The causes of osteoclast failure are unclear but may involve abnormalities in the osteoclast stem cell or its microenvironment, osteoblast precursor cells or the mature heterokaryon or in the bone matrix. [28] Alterations in the factors required for bone resorption, such as the synthesis of abnormal PTH or defective production of IL-2 or superoxide, are also possible causes. Ultimately, impaired bone resorption results in skeletal fragility because fewer collagen fibrils connect osteons properly, and remodeling of woven bone to compact bone is defective [Figure 6]. [28]
Figure 6: Osteopetrosis

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Role in myeloma bone disease

Myeloma bone disease is due to interactions of myeloma cells with the bone marrow microenvironment and is associated with pathologic fractures, neurologic symptoms, and hypercalcemia. Adjacent to myeloma cells, the formation and activation of osteoclasts are increased, which results in enhanced bone resorption. [29] Malignant tumors capable of either forming skeletal metastases or causing hypercalcemia utilize the cellular machinery (osteoclasts) and molecular pathways (RANKL/RANK/OPG) of normal bone cell biology. [30] Focally or systemically enhanced osteoclastic activation results in tumor-associated hypercalcemia, osteolysis, pathologic fractures, and severe pain. [31] Increased expression of RANKL by bone marrow stromal cells was associated with enhanced osteoclastogenesis, and this effect could be prevented by RANK-Fc, a specific inhibitor of RANKL. Taken together, enhancement of marrow stromal (and possibly T cell) expression of RANKL by myeloma cells and direct RANKL expression by myeloma cells contribute to enhanced osteoclastogenesis in the bone microenvironment in myeloma bone disease. [30]

Role in osteoarthritis

The articular joint is made up of several tissues, the main ones involved during osteoarthritis (OA) being the cartilage, synovial membrane, and subchondral bone, all of which are closely linked. The cartilage is the tough elastic material that covers and protects the ends of bone. In a healthy joint, it acts as a shock absorber when weight is exerted on the joint and its slippery surface allows the joints to move smoothly. Joint degeneration does occur, however, and OA is the most common joint disorder, affecting about 65% of individuals over 60 years of age. [32] In OA, a subchondral bone resorption/formation process has been shown to occur, in which there are phases of bone degradation and others of bone formation. Interestingly, factors such as OPG and RANKL, which constitute specific components capable of influencing the bone remodeling process, have been found to be expressed and modulated in human OA subchondral bone. In addition to subchondral bone, the OPG/RANK/RANKL triad has also been observed to be expressed by the other articular cells. Indeed, articular chondrocytes also express each factor. OPG, RANK, and RANKL have been detected in the superficial zone of normal cartilage whereas during OA, their expression was found to extend to the middle zone. [33]

Role in neoplasia

In neoplasia, bone remodeling can be disturbed as a result of increased bone turnover which may be confined to the site of metastases or be more generalized, most likely related to the secretion of PTHrP or other factors by the primary tumor. A significant increase in bone turnover is not uncommon and may result in substantial skeletal deficits, more marked at trabecular cancellous sites. Bone remodeling may also be disturbed due to an imbalance between bone resorption and formation. Most of the disturbances in bone remodeling associated with neoplasia result in significant amounts of bone loss not uncommonly associated with hypercalcemia. [34]

Role in osteoporosis

Osteoporosis is defined as a decrease in bone mass coupled with a disorder in bone microarchitecture associated with as clinical consequence an increase in the risk of fracture. Fundamental to the pathogenesis of osteoporosis is an aberrant cell production relative to demand. In age-related osteoporosis, there is an undersupply of osteoblasts relative to the needs for repair due to a decrease in osteoblastogenesis. Bisphosphonates correct the imbalance between bone resorption and formation, and the role of these agents is now established in the management of osteoporosis. [33]

Role in cyst enlargement

The most prominent destructive event connected with radicular cyst is the resorption of alveolar bone. The effector cells of this process are osteoclasts. Activated osteoclast will resorb the mineralized matrix and degrade organic components of bone. [34]

The RANKL and OPG can be identified in radicular cysts. Menezes et al. have identified the expression of both molecules in radicular cysts, with the number of RANKL being higher than OPG (the ratio of RANKL/OPG: 1.40 ± 0.04). Both RANKL and OPG are involved in osteoclasts signaling. [34]

Bone resorption is a complex process involving highly coordinated interactions between osteoblasts and osteoclasts that are modulated by the RANKL/RANK/OPG system. RANKL is secreted primarily by activated T-cells and binds a cell surface receptor (RANK) to promote osteoclast differentiation and activation. Tay et al. showed immunostaining for RANKL within the fibrous wall of radicular cysts. That RANKL involved in osteoclast recruitment was confirmed by the demonstration of TRAP and calcitonin-receptor-positive osteoclasts adjacent to the RANKL-positive cells. [35]

  Conclusion Top

Bone remodeling is a fine-tuned process insuring the maintenance of skeletal mass and integrity. Osteoclast and odontoclast functions are closely related to physiological and pathological clinical scenarios including craniofacial abnormalities, tooth eruption, and root resorption. Understanding the complex mechanisms that control osteoclast or odontoclast development and activation will provide insights in early detection and management of clinical challenges. The above disorders represent a few examples of the consequences of disturbances in this physiologically complex but carefully coordinated process on skeletal metabolism. Future translational studies should be carried out to elaborate how to modulate osteoclast or odontoclast function at the molecular level and develop therapeutic strategies to turn on or off osteoclastogenesis or odontoclastogenesis activation pathways and hence provide therapeutics for promoting bone remodeling or inhibiting bone resorption.

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Conflicts of interest

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]


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