Table 1.

Summary table of the effects of boron, cadmium, copper, iron, magnesium, manganese, selenium, and zinc on osteoarthritis.

Element	Function	Mechanism	References
Boron	Supplementation: Preventing OA; Alleviating pain and discomfort; Reducing inflammation; Improve joint function; Repairing osteochondral defects; Deprivation: Decreasing chondrocyte density	Downregulating some enzyme activities; Inhibiting inflammatory response, reducing inflammatory cytokines; Enhancing antioxidant defense; Improving absorption of calcium, phosphorus and magnesium, and retention of calcium and magnesium	(21, 22, 26–35)
Cadmium	Increase risk of OA; Inducing cartilage degradation, resulting in osteophyte formation, subchondral sclerosis, synovitis	Reducing proteoglycan and glycosaminoglycan, inhibiting aggrecan and COL II; Producing IL-1β and IL-6, activating MMPs, destroying ECM; Aggravating homeostasis imbalance; Promoting production of ROS; Displacing essential elements, such as zinc, iron, copper, manganese, nickel, chromium	(36–43)
Copper	Relieving OA symptom; Promoting cartilage injury healing; Enhancing cartilage formation; Promoting articular cartilage and subchondral bone regeneration;	Activating cartilage immune response; Enhancing anti-inflammatory cytokine secretion, inhibiting inflammatory response, reducing cartilage tissue lesion; Restraining NO release, enhancing anti-catabolism; Improving collagen cross-linking, enhancing COL II synthesis; Increasing chondrocyte viability; Promoting chondrocyte proliferation and maturation; Raising chondrogenic gene expression, enhancing chondrogenesis differentiation of MSCs	(44–51)
	Deficiency: Destroying cartilage integrity; Increasing incidence of OA; Excess: Developing early-onset OA	Impairing cross-linking between collagen and elastin, weakening cartilage	(44, 52–54)
		Raising oxidation capacity, damaging joint	(55, 56)
Iron	Excess: Impairing cartilage; Exacerbating pathogenesis and progression of OA	Releasing pro-inflammatory cytokines, triggering chondrocyte catabolism; Inducing hydroxyl radical driven chondrocyte apoptosis and matrix decomposition; Producing ROS, causing oxidative stress, activating MMPs, degrading ECM, reducing cartilage resistance; Reducing expression of transcripts for COL II and aggrecan, increasing transcriptional counts of pro-inflammatory cytokines, establishing OA-related phenotype	(57–70)
Magnesium	Relieving mechanical allodynia and thermal hyperalgesia; Alleviating pain; Reducing cartilage degeneration and articular cartilage lesion; Retarding OA progression;	Inhibiting inflammatory cytokines and neurotransmitters; Reducing chondrocyte apoptosis; Increasing synthesis of cartilage matrix, alleviating degeneration of cartilage matrix, inducing assembly of cartilage matrix, inhibiting expression of inflammatory cytokines and proteases, promoting adhesion of synovial MSCs and collagen, raising adhesion of human synovial MSCs to osteochondral defects; Enhancing formation of chondrocytes from synovial MSCs, promoting chondrocyte proliferation and improving effect of growth factor;	(71–80)
	Deficiency: Exacerbating progression of OA; Delaying cartilage and bone differentiation; Causing lack of orderly arrangement of chondrocyte columns, reducing bone formation	Elevating CRP; Increasing proinflammatory cytokines; Activating of immune response cells; Inducing fibroblasts senescence	(81–85)
Manganese	Relieving OA symptoms, improving imaging indicators; Retarding articular cartilage degeneration, Repairing cartilage; Alleviating OA severity	Enhancing synthesis of glycosaminoglycan, proteoglycan, and COL II; Regulating metabolism of cartilage matrix; Scavenging oxygen free radical and antioxidant, reducing oxidative stress; Enhancing chondrocyte viability, protecting ECM	(86–89)
	Deficiency: Causing cartilage dysplasia	Impairing glycosaminoglycan biosynthesis	(90)
Selenium	Enhancing cartilage regeneration, improving repair of metaphyseal injury	Scavenging ROS, improving immune system function, enhancing antioxidant defense, maintaining cartilage homeostasis and redox balance; Blocking expression of pro-inflammatory gene, reducing inflammatory response; Enhancing proliferation and differentiation of chondrogenic progenitor cells; Promoting proliferation of ATDC5 chondrogenic cells	(71–78, 83–85, 91, 92)
	Deficiency: Causing joint abnormality; Increasing risk for OA	Compromising cartilage metabolism; Inducing articular fibrocartilage formation, causing cartilage degradation; Inhibiting expression of chondrogenic genes SOX9, aggrecan, and COL II, reducing the alkaline phosphatase activity, disturbing chondrogenic differentiation of ATDC5 cells; Influencing chondrogenic differentiation of MSCs, affecting endochondral ossification; Impairing homeostasis of cartilage matrix	(78–80, 93, 94)
Zinc	Alleviating OA symptom; Preventing OA progression	Reducing expression of proinflammatory cytokines, possessing anti-inflammatory activity; Scavenging ROS, exerting antioxidant effect, alleviating oxidative injury; Activating Phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, increasing matrix synthesis, raising chondrocyte survival; Promoting expression of IL-10 mRNA, blocking expression of IL-1β mRNA and MMPs-13 protein, raising IL-10 levels, reducing MMPs-13 and IL-1β; Increasing chondrocyte proliferation, promoting differentiation of MSCs into chondrocytes, enhancing growth and maturation of cartilage;	(87–90, 95–97)
	Deficiency: Impairing cartilage maturation Excess: Damaging articular cartilage	Inhibiting multiplication of chondrocytes, resulting in chondrocytes disorganization;	(95)
		Up-regulating transcription of IL-6 and IL-11, inducing expression of MMPs, releasing cytokines and MMPs, causing articular cartilage injury and synovium; Activating ZIP8-Zn-MTF1 axis, increasing MMPs-13 synthesis, aggravating cartilage damage	(98–102)

OA, osteoarthritis; COL II, type II collagen; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-11, interleukin-11; ECM, extracellular matrix; MMPs, matrix metalloproteinases; ROS, reactive oxygen species; NO, nitric oxide; MSCs, mesenchymal stem cells; MTF1, metal regulatory transcription factor-1.