The origins and roles of osteoclasts in bone development, homeostasis and repair

Abstract

The mechanisms underlying bone development, repair and regeneration are reliant on the interplay and communication between osteoclasts and other surrounding cells. Osteoclasts are multinucleated monocyte lineage cells with resorptive abilities, forming the bone marrow cavity during development. This marrow cavity, essential to hematopoiesis and osteoclast-osteoblast interactions, provides a setting to investigate the origin of osteoclasts and their multi-faceted roles. This Review examines recent developments in the embryonic understanding of osteoclast origin, as well as interactions within the immune environment to regulate normal and pathological bone development, homeostasis and repair.

Keywords: Bone development; Hematopoietic stem cell; Osteoclast; Yolk sac.

Fig. 1.

Schematic showing the developmental origin of osteoclasts. Early erythromyeloid progenitors (EMPs; purple lineage) appear around E7-E7.5 in the yolk sac and differentiate into yolk-sac macrophages that give rise to tissue-resident macrophage populations, such as brain microglia. Late EMPs (pink lineage) emerge in the yolk sac at around E8.25-E9 and migrate to the fetal liver to produce fetal liver monocytes. These EMP-derived monocytes/macrophages can give rise to embryonic osteoclasts (OCLs), forming the bone marrow cavity around E15.5, which is necessary for hematopoiesis during development. Fetal hematopoietic stem cells (HSCs; blue lineage) emerge at E10.5 in the aorta-gonad-mesonephros (AGM) region and also migrate to the fetal liver, where they give rise to OCL precursors.

Fig. 2.

Complexity and variety of osteoclasts with multiple developmental origins. Schematic showing the diversity of osteoclasts. Early and late embryonic yolk-sac erythromyeloid progenitors (EMPs; purple and pink lineages, respectively) and fetal hematopoietic stem cells (HSCs; blue) can produce fetal monocyte-derived osteoclast progenitors. Postnatal bone marrow HSCs form monocytes/macrophages and dendritic cells (DCs) through continuous differentiation processes, which give rise to osteoclasts (green) (schematic based on Laurenti and Göttgens, 2018). Postnatal bone marrow HSC-derived, fetal HSC-derived and embryonic late EMP-derived osteoclast precursors fuse to form a diverse and complex osteoclast diversity (yellow multinucleated cells). CLP, common myeloid progenitor; CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitors; ILCs, innate lymphoid cells; LMPP, lymphoid-primed multipotent progenitor; MEP, megakaryocyte-erythrocyte progenitors; MLP, multi-lymphoid progenitor; NK, natural killer cells.

Fig. 3.

Osteoclast specification. (A) Osteoclast (OCL) fusion and maturation. The osteoclast fusion consists of sequential steps: (1) migration, (2) partner recognition, (3) adhesion and (4) fusion. Osteoclast progenitor cells reside in the bone marrow cavity proximal to vascular networks. Single-nucleated osteoclast precursors (shown with purple, orange and red nuclei) migrate from the bone marrow cavity to sites of resorption on the bone surface. Osteoclast progenitors selectively recognize their fusion partners, followed by cell-cell fusion and maturation. (B) Osteoclast-osteoblast-osteocyte interactions. Osteoblasts (OBs), osteocytes (OCs) and osteoclasts directly communicate each other through either cell-to-cell interaction or paracrine signaling molecules. Osteoblasts secrete M-CSF, RANKL and WNT5A to promote osteoclast differentiation. OPG, SEMA3A and WNT16 secreted by osteoblasts inhibit osteoclast differentiation. SEMA4D suppresses osteoblast differentiation. Osteocytes regulate the balance of bone formation and resorption by secreting RANKL/OPG. SOST from osteocytes interacts with LRP5/6 and suppresses preosteoblast differentiation via inhibitory effects on the WNT/β-catenin pathway. RANK-enriched vesicles secreted from osteoclasts can increase bone formation by triggering RANKL reverse signaling. HSC, hematopoietic stem cell.

Fig. 4.

Endochondral ossification and the skeletal stem cell niche. (A) Schematic of endochondral ossification and long bone development. Mesenchymal cells condensate and form primordial cartilage. Chondrocytes start to proliferate and then differentiate into hypertrophic chondrocytes with the mineralization. The diaphysis is separated by the primary ossification center with vascular invasion. Hypertrophic chondrocytes undergo apoptosis or are directly converted to osteoblasts. The secondary ossification center appears in the epiphysis, which is vascularized and forms the articular cartilage and epiphyseal growth plate. (B) The round-shaped resting-zone chondroprogenitors in the epiphysis are recruited into the proliferative columns during fetal bone development, leading to their gradual consumption. (C) After forming the secondary ossification center, PTHrP⁺ chondroprogenitors (yellow) are present in the resting zone; these cells start renewing and generate long columns from single clones. PTHrP⁺ skeletal stem cells can give rise to CXCL12⁺ LEPR⁺ bone marrow stromal cells (BMSCs; pink) and osteoblasts (blue). (D) CTSK⁺ (orange) and MX1⁺αSMA⁺ (green) skeletal stem cells in the periosteum, which can give rise to osteogenic cells.

Fig. 5.

Osteoclast maintenance and recycling. (A) Postnatal maintenance of osteoclasts in the long-lived syncytia occurs through the sequential acquisition of new nuclei from hematopoietic stem cell (HSC)-derived precursors in the blood. (B) Osteoclasts divide into smaller, more motile daughter cells called osteomorphs, which are recycled by fusing to form functional osteoclasts.

Fig. 6.

Schematic of trabecular (top) and cortical (bottom) bone remodeling. The bone remodeling cycle consists of overlapping phases: initiation, resorption, reversal, formation and termination. The lining cells and osteocytes (OCs) release local factors that attract osteoclast precursors from the perivascular and bone marrow niches to the remodeling compartment. Osteoclasts (OCLs) initiate bone resorption, followed by the breakdown and removal of old bone. Osteoclasts then begin to interact directly or indirectly with osteoblasts (OBs), which deposit osteoid and new lamellar bone. Osteoblasts trapped in the bone matrix differentiate into osteocytes, whereas others die or turn into quiescent lining cells on the bone surface. The resting bone environment is maintained until the next wave of remodeling cycle is initiated.