Osteoblast-Osteoclast Communication and Bone Homeostasis: Comparison
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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. 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 was reviewed.

  • bone
  • osteoblast
  • osteoclast

1. Soluble Factors Released from Osteoblasts

1.1. Macrophage Colony-Stimulating Factor (M-CSF)

M-CSF (also called as CSF1) is a hematopoietic growth factor that allows for survival, proliferation, differentiation, and mobility of mononuclear phagocyte lineages, including osteoclasts [43,44][1][2]. M-CSF, secreted from osteoblasts and bone marrow stromal cells, binds to its cognate receptor C-FMS on the surface of osteoclasts and monocytes/macrophages [45][3]. Osteopetrotic (op/op) mice where a thymidine insertion in the Csf1 gene resulted in M-CSF deficiency show decreased numbers of macrophages and osteoclasts at a young age. However, these phenotypes disappear during aging. Injection of recombinant M-CSF or production of soluble M-CSF in osteoblasts increases osteoclast numbers and rescues osteopetrotic phenotypes in op/op mice, demonstrating that M-CSF is crucial for osteoclast formation at least in young mice, but does not exclude the existence of M-CSF-independent compensatory mechanisms.

1.2. Receptor Activator of NF-κB (Nuclear Factor-Kappa B) Ligand (RANKL)

RANKL is also called osteoclast differentiation factor (ODF), TNF ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), and OPG ligand (OPGL) [46,47][4][5]. RANKL is highly expressed in osteoblasts, osteocytes, activated T lymphocytes, and lymph nodes [48,49,50][6][7][8]. RANKL binds to its cognate receptor, receptor activator of NF-κB (RANK) on the surface of osteoclasts and osteoclast precursors, leading to osteoclast differentiation, fusion, and activation [6,51][9][10]. Mice deficient in Tnfrsf11a (RANK) or Tnfsf11 (RANKL) are phenocopies of one another, indicating the essential role of this RANKL/RANK signaling axis in bone remodeling [48,51][6][10]. Deletion of RANKL in mice results in severe osteopetrosis due to absence of osteoclasts, whereas overexpression of soluble RANKL leads to severe osteoporosis [48,52][6][11]. Accordingly, blocking RANKL signaling has been proposed as a promising therapeutic target for osteoporotic bone loss and related skeletal disorders.

1.3. Osteoprotegerin (OPG)

OPG is also known as osteoclastogenesis inhibitory factor (OCIF) and TNF receptor superfamily member 11B (TNFRSF11B) [47,53,54][5][12][13]. OPG was identified as a secreted glycoprotein synthesized by many types of cells, including osteoblasts, lung- or liver-residing cells, and B lymphocytes in the bone marrow [53,54,55][12][13][14]. Overexpression of OPG results in profound osteopetrosis due to inhibition of osteoclast formation, whereas Tnfrsf11b (OPG)—deficient mice exhibit rapid postnatal bone loss and severe bone porosity due to an increased osteoclast development [53,56][12][15]. OPG is considered to function as a decoy receptor binding to RANKL, negatively regulating osteoclast differentiation and activation by blocking the RANKL-RANK interaction [6,57][9][16].

1.4. WNT5A

The WNT pathway is crucial for the maintenance of bone homeostasis by regulating osteoblastogenesis and osteoclastogenesis through both β-catenin-dependent (canonical) and -independent (noncanonical) pathways [58][17]. A noncanonical WNT ligand, WNT5A, is highly expressed in osteoblast-lineage cells and binds to its cognate receptor, receptor tyrosine kinase-like orphan receptor 2 (ROR2), on the surface of osteoclasts [59][18]. Heterozygous deletion of Wnt5a or Ror2 in mice resulted in impaired development of bone marrow-derived monocytes (BMM) to mature osteoclasts. Corresponding defects in osteoclastogenesis were also observed in mice with osteoblast-specific deletion of Wnt5a or osteoclast-specific deletion of Ror2. WNT5A enhances RANKL-induced osteoclastogenesis by upregulating RANK expression in osteoclasts via activation of the Jun–N-terminal kinase (JNK) MAPK pathway.

1.5. WNT16

The WNT16 locus is closely associated with bone mineral density (BMD), cortical bone thickness, and fracture risk in humans [60,61,62][19][20][21]. WNT16 is highly expressed in osteoblast-residing cortical bone, but little to no expression is detected in osteoclasts [63][22]. Global deletion of Wnt16 results in a specific decrease in cortical bone mass and an increase in cortical porosity, along with spontaneous fractures where there is no alteration in trabecular bone. WNT16 suppresses osteoclastogenesis in both a direct and indirect manner. In addition to direct inhibition of osteoclastogenesis via the noncanonical JNK MAPK pathway, WNT16-induced phosphorylation of JUN upregulates expression of OPG in osteoblasts, providing a direct mechanism to suppress osteoclastogenesis. Osteoblast-specific deletion of Wnt16 in mice phenocopies mice with its global deletion, suggesting osteoblasts are a primary source of WNT16, with an impact on cortical bone and skeletal integrity. Table 1 provides a list of osteoblast-derived factors that regulate osteoclasts.
Table 1. Summary of the effect of osteoblast-derived factors on osteoclast behavior.
Summary of the effect of osteoblast-derived factors on osteoclast behavior.
 
Osteoblast-Derived Factor Mode of Action Influences on Osteoclasts References
EFNB2 Membrane-bound Inhibits osteoclastogenesis [26][23]
FASL Membrane-bound Induces osteoclast apoptosis [36][24]
SEMA3A Membrane-bound Inhibits RANKL-induced osteoclastogenesis [38][25]
M-CSF Secreted Promotes proliferation and survival of osteoclast precursor [45][3]
RANKL Membrane-bound and secreted Promotes osteoclast differentiation and activation [6,][9]51[10]
OPG Secreted Inhibits osteoclastogenesis [6,57][9][16]
WNT5A Secreted Promotes osteoclastogenesis [58][17]
WNT16 Secreted Inhibits osteoclastogenesis [63][22]

2. Impact of Therapeutic Agents on Osteoblast-Osteoclast Interactions

Despite there being many factors identified that regulate osteoblast-osteoclast interactions, currently very few of these pathways have resulted in approved therapeutics for the treatment of skeletal disorders. However, osteoblast–osteoclast interactions have played a powerful role in shaping the action of all currently approved drugs acting on the skeleton, including often imposing limitations on the activities of these agents. Most anti-resorptive agents inhibiting osteoclast formation and activity simultaneously suppress bone formation, whereas the activity of anabolic agents inducing bone formation are similarly tempered by simultaneously increasing bone resorption.
Denosumab is a humanized monoclonal antibody that binds RANKL and acts as an OPG-like RANK decoy receptor, disrupting the RANKL-RANK interaction and osteoclast differentiation, function, and survival, leading to a decrease in bone resorption. In patients, biannual administration of Denosumab increases bone density, and reduces the risk of vertebral, nonvertebral, and hip fractures [82][26]. However, as expected, inhibiting osteoclast formation by blocking RANKL-RANK signaling pathway results in reduction of osteoclast-derived coupling factors that induce osteoblast-mediated bone formation. Denosumab leads to an immediate and sustained decrease in markers of bone resorption such as urinary N-telopeptide (NTX) along with a delayed reduction in markers of bone formation, such as serum bone specific alkaline phosphatase (BSAP) [83,84][27][28].
Odanacatib, a selective cathepsin K (CTSK) inhibitor, suppresses osteoclast-mediated bone resorption [85,86][29][30]. CTSK is a cysteine proteinase, abundantly expressed in activated osteoclasts and secreted to extracellular space that cleaves the N-telopeptide of collagen [87][31]. CTSK mutation in humans causes pycnodysostosis, a rare skeletal dysplasia, characterized by short stature, an increase in the bone density of long bones, acroosteolysis of distal phalangers and skull deformities [88][32]. Despite the high bone mass phenotype, patients with pycnodysostosis suffer from bone fragility with a high incidence of pathological fractures [89][33]. Odanacatib has received a lot of attention as a potential osteoporosis drug since it inhibits osteoclast activity and function, rather than osteoclast generation, resulting in prevention of bone resorption with more modest overall effects on the ability of osteoblasts to form bone than most other anti-resorptive agents. It still remains unclear whether these effects reflect functional blockade of osteoclast-driven coupling processes or whether CTSK inhibition may have direct effects on CTSK-expressing periosteal mesenchymal progenitors [90,91][34][35]. Although odanacatib was highly effective in reducing fractures of postmenopausal women in clinical phase-3, its further development was discontinued due to concerns regarding risk of cerebrovascular events [92][36].
Parathyroid hormone (PTH), a bone anabolic agent, is normally secreted by the parathyroid glands and contributes to the maintenance of calcium homeostasis through its direct actions on bone cells. Intermittent PTH administration increases bone mass by recruiting mesenchymal stromal cells into osteoblast lineage and promoting the differentiation of osteoprogenitors into mature osteoblast [93,94][37][38]. Also, PTH downregulates sclerostin (SOST) expression from osteocytes, leading to a favorable environment for osteoblast differentiation and function through enhanced WNT signaling pathway [95,96][39][40]. However, continuous treatment results in an increase in net bone resorption due to increases in RANKL and decreases in the RANKL decoy receptor, OPG, in osteoblasts and osteocytes [97][41]. As seen in each of these examples, one of the most fundamental and enduring challenges in developing increasingly effective skeletal therapeutics is overcoming the osteoblast/osteoclast interaction effects that often blunt the activity of both anti-resorptive and anabolic drugs.
 

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