Bone resorption goes green

In this issue of Cell, McDonald et al. show that giant multinucleated, bone-resorbing osteoclasts dissolve into smaller cells, termed “osteopmorhs,” which re-form at distal bone sites (McDonald al., 2021McDonald M.M. Khoo W.H. Ng P.Y. Xiao Y. Zamerli J. Thatcher P. Kyaw W. Pathmanandavel K. Grootveld A.K. Moran I. al.Osteoclasts recycle via osteomorphs during RANKL-stimulated resorption.Cell. 2021; 184 (this issue): 1330-1347.e13Abstract Full Text PDF PubMed Scopus (42) Google Scholar). These findings overturn the long-standing premise differentiate solely from hematopoietic precursors and undergo apoptosis after completing resorption. The osteoclast is unique in its ability to remove old bone. This resorptive function matches precisely requirements skeletal morphogenesis, modeling, remodeling. latter, a process described by orthopedic surgeon John Hunter as early 1743, defined constant removal replenishment an equal amount new osteoblast (Hunter, 1743Hunter On structure diseases articulating cartilages.Phil. Trans. R. Soc. 1743; 42: 514-522Crossref Enhanced osteoclastic resorption, reduced osteoblastic formation, or combination both results net loss bone, osteoporosis metastasis—and consequently, high risk fracture (Zaidi, 2007Zaidi M. Skeletal remodeling health disease.Nat. Med. 2007; 13: 791-801Crossref (720) Much our current understanding biology originates studies 1970s demonstrating through parabiosis experiments are derived cells (Buring, 1975Buring origin heterotopic formation.Clin. Orthop. Relat. Res. 1975; : 293-301Crossref (112) Subsequently, two key cytokines were discovered be necessary sufficient for formation cells: macrophage colony-stimulating factor (M-CSF) receptor activator nuclear κB ligand (RANKL) (Lacey 1998Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott Colombero A. G. Scully S. al.Osteoprotegerin cytokine regulates differentiation activation.Cell. 1998; 93: 165-176Abstract (4474) underscore concept monocytic lineage fuse together form terminally differentiated multinuclear polykaryons no longer have proliferate but can resorb (Zaidi 2018Zaidi Yuen Sun L. Rosen C.J. Regulation homeostasis.Endocr. Rev. 2018; 39: 701-718Crossref (33) lifespan thought relatively short, around 2 3 weeks, with their demise resulting following cessation resorption given site. However, contemporary work rodents has called question view fleeting osteoclasts. using genetically modified mice expressed different fluorescent markers, it was shown recently one animal not only became incorporated other animal, had been 1970’s, nuclei continued present up 6 months animals separated (Jacome-Galarza 2019Jacome-Galarza C.E. Percin G.I. Muller J.T. Mass Lazarov Eitler Rauner Yadav V.K. Crozet Bohm al.Developmental origin, functional maintenance genetic rescue osteoclasts.Nature. 2019; 568: 541-545Crossref (142) challenged supported alternative notion they instead long-lived cells. If enduring transitory nature, what happens needed site? Similarly, how ones formed needing resorption? To help address these questions, Scholar developed novel technique reporters image fate tibias adult Specifically, repleted marrows irradiated donor mice––one tdTomato LYSM+ myeloid engineered express GFP driven either Csf1r Blimp-1 promoters. fusion multinucleate allowed them tracked signals. Using technique, authors able penetrate cortex mouse find stellate appearance underwent dynamic fission events smaller, motile daughter “osteomorphs.” then observed migrate nearby balanced process, where 1% per hour experienced event. phenomenon new, having first 1980s (Baron Vignery, 1981Baron Vignery Behavior rapid change number induced doses parathyroid hormone calcitonin intact rats.Metab. Bone Dis. 1981; 2: 339-346Abstract (63) remained largely unstudied. determine whether osteoporphs acquired distinct transcriptomic architecture osteoclasts, performed single-cell RNA sequencing on flow cytometry-sorted mononuclear previously resorbed vivo, evidenced uptake third marker, bisphosphonate zolendronic acid. They found transcriptional program, marrow expressing many traditional genes, such Ctsk (cathepsin K), Acp5 (tartrate-resistant acid phosphatase, TRAP), Nfatc1 (NFAT2), overall concordance 75% between Nonetheless, 151 genes Loss-of-function mutations certain osteomorph-specific bisphosphoglycerate mutase (Bpgm) F-box protein 7 (Fbxo 7), known produce phenotypes mice. suggest targeted specifically yield functional, possibly therapeutic, outcomes. Notwithstanding distinctions, molecular regulation yet examined. There does appear easy way extract marrow, will complicate future efforts study note displayed higher expression than cell-surface markers AXL, CD11b, CCR3, VCAM1, CD74, CADM1; however, remains seen if used separate One interesting avenue potential exploration arises fact circulate bloodstream. Potential targeting control arterial plaques, osteoclast-like (Qiao 2015Qiao J.H. Mishra V. Fishbein M.C. Sinha S.K. Rajavashisth T.B. Multinucleated atherosclerotic plaques human carotid arteries: Identification specific proteins artery wall.Exp. Mol. Pathol. 2015; 99: 654-662Crossref (22) Scholar), may unravel avenues treatment disease. next began ask conservation bears relevance therapeutics. accumulate within upon OPG:Fc, agent blocks RANKL closely mimics actions FDA-approved therapeutic denosumab. Upon withdrawal inhibition, rapidly fused osteoclasts—a finding helps explain sharp increases discontinuation denosumab therapy people (Anastasilakis 2020Anastasilakis A.D. Evangelatos Makras Iliopoulos Rebound-associated vertebral fractures occur sequential time points discontinuation: need prompt re-initiation.Bone Rep. 2020; 12: 100267Crossref (15) further reiterates suggestion should followed apoptosis-inducing agent, bisphosphonate, prevent fusing rebound loss. summary, uncovers cellular program reuse notably dissolution, transport, reassembly (Figure 1). We expect discovery usher wave greater insights physiology, well unmask actionable targets phases life cycle. M.Z. inventor various patents, filed approved, FSH, body composition—these patents held Icahn School Medicine Mount Sinai, receive royalties, arise, accordance Medical policy. related manuscript. Osteoclasts resorptionMcDonald al.CellFebruary 25, 2021In BriefTracking cycles reveals transcriptionally “osteomorph” population competent, motile, capable forming Full-Text Open Access