Osteocytes regulate senescence of bone and bone marrow

Abstract

The skeletal system contains a series of sophisticated cellular lineages arisen from the mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), that determine the homeostasis of bone and bone marrow. Here we reasoned that osteocyte may exert a function in regulation of these lineage cell specifications and tissue homeostasis. Using a mouse model of conditional deletion of osteocytes by the expression of diphtheria toxin subunit 𝛼 (DTA) in dentin matrix protein 1 (DMP1) positive osteocytes, we demonstrated that partial ablation of DMP1 positive osteocytes caused severe sarcopenia, osteoporosis and degenerative kyphosis, leading to shorter lifespan in these animals. Osteocytes reduction altered mesenchymal lineage commitment resulting in impairment of osteogenesis and induction of osteoclastogensis. Single cell RNA sequencing further revealed that hematopoietic lineage was mobilized towards myeloid lineage differentiation with expanded myeloid progenitors, neutrophils and monocytes, while the lymphopoiesis was impaired with reduced B cells in the osteocyte ablation mice. The acquisition of a senescence-associated secretory phenotype (SASP) in both osteoprogenic and myeloid lineage cells was the underlying cause. Together, we showed that osteocytes play critical roles in regulation of lineage cell specifications in bone and bone marrow through mediation of senescence.

Myeloid Cells As a Promising Target for Brain–Bone Degenerative Diseases from a Metabolic Point of View

“…[ 53,55,95,96 ] Nevertheless, we recently found that depletion of osteocytes, the most abundant cells within bone matrix and the central hub of bone metabolism, lead to increased osteoclastogenesis and myelopoiesis. [ 97 ] Moreover, elevated senescence of bone marrow immune cells was detected on transcriptomic level. [ 97 ] It is established that decreased osteocyte density and impairment of the osteocyte network could be a sign of osteoporosis, osteoarthritis and aging.…”

“…[ 97 ] Moreover, elevated senescence of bone marrow immune cells was detected on transcriptomic level. [ 97 ] It is established that decreased osteocyte density and impairment of the osteocyte network could be a sign of osteoporosis, osteoarthritis and aging. [ 98–100 ] Thereby, osteocyte could contribute to myeloid cell dysfunction in aging and osteoporosis.…”

Down-expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenesis and accelerates age-related bone loss via PTEN/PI3K/AKT pathway

“…23,24 Changes in osteocytes and their regulatory functions related to osteoblasts, osteoclasts, and bone marrow-derived mesenchymal stem cells (BMSCs) during disease progression have been investigated. [25][26][27] Inhibition of cellular senescence, especially osteocyte senescence, represents a new therapeutic paradigm for age-related osteoporosis. Researchers have proven that specific clearing of senescent osteocytes by genetic or pharmacological approaches can prevent age-related bone loss in mice.…”

The effect of osteocyte‐derived RANKL on bone graft remodeling: An in vivo experimental study

“…Most of our present knowledge about the role of osteocytic signaling, including the role of RANKL expression in osteocytes, is derived from murine Cre/loxP conditional knockout systems (Kim et al, 2018) utilizing dentin matrix phosphoprotein 1 (Dmp1) (Chicana et al, 2022;Ding et al, 2022;Fujiwara et al, 2016;Graves et al, 2018;Lim et al, 2021;Nakashima et al, 2011;Shoji-Matsunaga et al, 2017;Xiong et al, 2011;Xiong et al, 2014;Xiong et al, 2015).…”

“…Most of our present knowledge about the role of osteocytic signaling, including the role of RANKL expression in osteocytes, is derived from murine Cre/loxP conditional knockout systems (Kim et al, 2018) utilizing dentin matrix phosphoprotein 1 (Dmp1) (Chicana et al, 2022; Ding et al, 2022; Fujiwara et al, 2016; Graves et al, 2018; Lim et al, 2021; Nakashima et al, 2011; Shoji‐Matsunaga et al, 2017; Xiong et al, 2011; Xiong et al, 2014; Xiong et al, 2015). Dmp1 is an extracellular matrix protein that is present in dental and bone tissue where it is primarily expressed by odontoblasts as well as mature osteoblasts and osteocytes, respectively (Fen et al, 2002; George et al, 1993; Komori, 2014; Toyosawa et al, 2001).…”