Osteocytes are increasingly recognized as multifunctional cells that help orchestrate bone and mineral metabolism— and are currently one of the hottest topics in the field. In addition to their putative role as detectors/transducers of mechanical strain in bone, osteocytes are a major source of sclerostin, a key inhibitor of Wnt signaling and bone formation, and appear to be important regulators of osteoclast function via their production of NF‐kB ligand (RANKL) and osteoprotegerin. It has also long been believed that osteocytes could remove or even replace mineralized bone around their lacunae and canaliculi. Thanks to a number of studies and reviews in recent years, this once‐ controversial concept of “osteocytic osteolysis” is now verymuch back on the agenda. In this issue of the Journal of Bone and Mineral Research, Kogawa and colleagues present evidence that sclerostin could act to stimulate the dissolution of bone mineral by osteocytes by increasing their expression of some of the same resorptive machinery used by osteoclasts. The authors show that treatment of cultured MLO‐Y4 and primary human osteocyte‐like cells with recombinant human sclerostin increased the expression of mRNA for a number of resorptionmarkers, most notably carbonic anhydrase 2 (CA2). The authors found that sclerostin caused both intracellular and extracellular acidification in cultures of the osteocyte‐like cells, albeit in a non–dose‐dependentmanner. The classic CA inhibitor, acetazolamide decreased the sclerostin‐ stimulated extracellular acidification in MLO‐Y4 cells, whereas antisense knockdown of CA2 led to an extracellular alkalinization, with elimination of the effect of acetazolamide. Sclerostin additionally caused a slight stimulation of calcium release from mineralized layers of primary osteocyte‐like cells, an effect that was also blocked by acetazolamide. Stimulation of mRNA for CA2, tartrate‐resistant acid phosphatase (TRAP), chloride channel 7 (CLCN7), and cathepsin K by sclerostin in the MLO‐Y4 cell line was inhibited by small interfering RNA (siRNA) constructs for Lrp4, Lrp5, or Lrp6, suggesting the possible involvement of Wnt signaling. Last, sclerostin treatment increased the plan area of osteocyte lacunae by about 25% in cultured samples of trabecular bone taken from patients undergoing hip surgery, an effect that was again abrogated by acetazolamide. The concept of osteocytic osteolysis was first mooted in 19th century, although is perhaps now most closely associated with Belanger. He suggested that either parathyroid hormone (PTH) or a low‐calciumdiet can induce osteocytes to enlarge their lacunae. In its broadest sense, the term osteocytic osteolysis implies dissolution of not only the mineral component of bone adjacent to lacunae and canaliculi but of the collagenous matrix, too. These ideas provoked vigorous rebuttals but began to gain traction again following reports that osteocyte lacunar area wasmarkedly increased in rats continuously infused with PTH for 4 weeks and in mice infused with prednisolone for 3 weeks. Moremodest increases in lacunar sizewere also observed inmice subjected to ovariectomy. More recently, some of the coauthors of the paper by Kogawa and colleagues have presented a comprehensive study of the effects of lactation on osteocyte lacunae in mice. Lactation was shown to be associated with increases in lacunar area of about 20–40% in tibias and lumbar vertebrae; these increases were reversed with 7 days of cessation of lactation. The effects were mimicked by PTH‐related protein (PTHrP) and abrogated by targeted deletion of PTH receptor 1. Increased expression of mRNAs for osteoclast‐specific markers (including cathepsin K, which cleaves collagen) was also noted in “osteocyte‐enriched” bones of lactating animals. These reversible changes in osteocyte lacunar size have been referred to as “remodeling,” although this process clearly differs from bone remodeling by osteoclasts and osteoblasts, which involves obvious turnover of substantial quantities of both mineral and organic matrix. Despite suggestions that removal and replacement of collagenous matrix around osteocytes might occur in extreme pathophysiological situations, such as in the ultra‐high turnover bone of egg‐ laying hens, there seems to be little wider evidence for such a process. Removal of mineral alone might be sufficient to account for the enlargement of osteocyte lacunae observed by light or scanning electron microscopy if the resulting thin layer of demineralized collagenous matrix shrinks back against the lacunar walls during dehydration for specimen preparation. In vivo, such a layer of demineralized (hydrated) matrix adjacent to the osteocyte could presumably serve as a scaffold to facilitate
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Jul 29, 2023
Chong Chen + 4
Open Access