Exercise to Mend Aged-tissue Crosstalk in Bone Targeting Osteoporosis & Osteoarthritis

Abstract

Aging induces alterations in bone structure and strength through a multitude of processes, exacerbating common aging- related diseases like osteoporosis and osteoarthritis. Cellular hallmarks of aging are examined, as related to bone and the marrow microenvironment, and ways in which these might contribute to a variety of age-related perturbations in osteoblasts, osteocytes, marrow adipocytes, chondrocytes, osteoclasts, and their respective progenitors. Cellular senescence, stem cell exhaustion, mitochondrial dysfunction, epigenetic and intracellular communication changes are central pathways and recognized as associated and potentially causal in aging. We focus on these in musculoskeletal system and highlight knowledge gaps in the literature regarding cellular and tissue crosstalk in bone, cartilage, and the bone marrow niche. While senolytics have been utilized to target aging pathways, here we propose non-pharmacologic, exercise-based interventions as prospective "senolytics" against aging effects on the skeleton. Increased bone mass and delayed onset or progression of osteoporosis and osteoarthritis are some of the recognized benefits of regular exercise across the lifespan. Further investigation is needed to delineate how cellular indicators of aging manifest in bone and the marrow niche and how altered cellular and tissue crosstalk impact disease progression, as well as consideration of exercise as a therapeutic modality, as a means to enhance discovery of bone-targeted therapies.

Keywords: Adipocyte; Aging; Chondrocyte; Exercise; Hematopoietic stem cell (HSC); Loading; Marrow adipose tissue (MAT); Mechanical; Mesenchymal stem cell (MSC); Niche; Osteoarthritis; Osteoblast; Osteoclast; Osteoporosis; Senescence.

Figure 1.. Aging Weakens Osteogenic Output from Mesenchymal Stem Cells (MSC)

(A) Aged MSC favor adipogenesis over osteogenesis with reduced self-renewal, proliferation, and total MSC number, and increased ROS and SASP. (B) Aged Osteoblast number / activity is reduced, potentially mediated by ROS, adipokines, and SASP. (C) Aged Osteocyte morphology and the lacunocanalicular network are impaired, with increased ROS. (D) Marrow adiposity increases with aging, as well as excess ROS, adipokines, and the SASP. (E) Aged Chondrocyte senescence is enhanced. MSC, mesenchymal stem cell; OB, osteoblast; Ot, osteocyte; BMAd, bone marrow adipocyte; Ct, chondrocyte; ROS, reactive oxygen species; Mt, mitochondria; SASP, senescence-associated secretory phenotype

Figure 2.. Hematopoietic Differentiation Skews from Lymphoid to Myeloid with Aging.

(A) Hematopoietic stem cells (MSC) exhibit an age-related shift in terminal differentiation to favor myeloid over lymphoid cells. This occurs alongside reduced self-renewal, proliferation, and total HSC number, as well as enhanced production of ROS and SASP. (B) Osteoclast number and activity are greater in aging, while senescent osteoclasts and ROS accumulate. Notably, senescence does not appear to impair osteoclast function. HSC, hematopoietic stem cell; OC, osteoclast; ROS, reactive oxygen species; Mt, mitochondria; SASP, senescence-associated secretory phenotype.

Figure 3.. Exercise Effects on Mesenchymal & Hematopoietic Lineage Cells.

Summary of the effects of exercise or mechanical loading on mesenchymal (i.e., MSC, osteoblasts, osteocytes, marrow adipocytes, chondrocytes) and hematopoietic (i.e., HSC, osteoclasts) lineage cells in the bone marrow microenvironment. MSC, mesenchymal stem cell; OB, osteoblast; Ot, osteocyte; BMAd, bone marrow adipocyte; Ct, chondrocyte; ECM, extracellular matrix

Figure 4.. Overview of Aging & Exercise Modulation of Tissue Crosstalk in Bone.

(A) SASP production, a product of cellular senescence, is increased with aging. Alongside spreading senescence to neighboring cells via paracrine signaling, SASP production exerts direct effects on various niche cells which yield downstream alterations in cellular and tissue crosstalk. SASP production promotes stem cell exhaustion of HSC and MSC, as evidenced by lineage skewing and reduced cell cycle activity. As a pro-inflammatory stimulus, the SASP impairs osteogenesis and mineralization, while promoting osteoclastogenesis and resorption. Together, these changes combine to significantly alter the physical structure of the niche and tissue-level crosstalk. Exercise combats these changes through suppression of the SASP and direct and indirect cell-specific interactions, leading to a reduction in pro-inflammatory stimuli and enhanced anabolic activity. (B) ROS production, a product of mitochondrial dysfunction, is increased with aging. Excess ROS induces cellular damage in chondrocytes, making chondrocytes more susceptible to senescence. Increased ROS in the bone marrow niche alters cellular signaling cascades, yielding inhibition of osteogenic differentiation of MSC while enhancing adipogenesis and osteoclastogenesis. Exercise improves ROS defense mechanisms both systemically and locally in tissues directly engaged by exercise, such as muscle and weight-bearing bones. Improved ROS defense reduces ROS levels, preventing ROS-dependent alterations in cellular and tissue crosstalk. MSC, mesenchymal stem cell; OB, osteoblast; BMAd, bone marrow adipocyte; Ct, chondrocyte; HSC, hematopoietic stem cell; OC, osteoclast; SASP, senescence-associated secretory phenotype; ROS, reactive oxygen species.